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QP190  .M42  Physiology  of  secret 


THE  PHYSIOLOGY 


RECAP 


SECRETION. 


ALBERT    P.    MATHEWS. 


Submitted  in  Partial  Fulfilment  of  the  Requirements  for 

THE  Degree  of  Doctor  of  Philosophy  in  the  Faculty 

of  Pure  Science,  Columbia  University. 


[Reprinted  from  Annat.s  N.  Y.  Acad.  Sci.,  XI,  No.  14,  pp.  293-368.] 


LANCASTER,  PA. 
The  New  Era  Printing  Comp.\ny, 
",  1898. 


THE  i.ienAK. 


CIPI9D 


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THE  PHYSIOLOGY 


SECRETION. 


ALBERT   P.    MATHEWS. 


Submitted  in  Partial  Fulfilment  of  the  Requirements  for 

THE  Degree  of  Doctor  of  Philosophy  in  the  Faculty 

OF  Pure  Science,   Columbia  University. 


[Reprinted  from  Annals  N.  Y.  Acad.  Sci.,  XI,  No.  14,  pp.  293-368.] 


NO  LONaCR  THE  PROPtHTY  Of 

LANCASTER,  PA.  _^,  «rr<*#^ 

THI  LIBRARY  OF  WNWiy 

The  New  Era  Printing  Company,       tMEOto»<c*L  mtrnt^ny,  N    y 
i8q8.  -  '     ■     . 


THEOLOGIC^l    SEMINARY, 


^     ALBERT   PRESCOTT    MATHEWS. 

S.  B.,  Massachusetts  Institute  of  Technology,  1892. 
Assistant  in  Biology,  Massachusetts  Institute  of  Technology,  1892-3. 
Fellow  in  Biology,  Columbia  University,  1893-5. 
Student   at  Cambridge  University,   England;    and    Marburg,   Ger- 
many, 1895-7. 
Student  at  Columbia  University,  1897-8. 
Assistant  in  Physiology,  Harvard  Medical  School,  Boston,  1898-9. 


PUBLICATIONS. 

1.  On  Wurtz's  Method  for  the  Differentiation  of  Bacillus  typhi  ab- 

dominalis  from  Bacillus  coli  communis.      Technology  Quar- 
terly, 1894. 

2.  Maturation,  Fertilization  and  Polarity  in  the  Echinoderm  Egg. 

New  Light  on  the  "  Quadrille  of  the  Centers."     With  E.  B. 
Wilson.     Journal  of  Morphology,  Vol.  X.,  1895. 

3.  The  Origin  of  Uric  Acid  in  the  Organism.      A  Review.     Ne7v 

York  Medical  Journal,  1896. 

4.  Internal    Secretions  Considered   in    Relation  to  Variation  and 

Development.     Science,  Vol.  V.,  1897. 

5.  The  Scope  and  Present  Position  of  Bio-chemistry.     American 

Naturalist,  Vol.  XXXI.,  1897. 

6.  Zur  Chemie  der  Spermatozoon.      Zeitschft.  filr  physiol.  Chemie, 

Bd.  XXIII. ,  1897. 

7.  Die   Verdanungsprodukte    des    Protamins.       With    A.    Kossel. 

Zeitschft.  filr  physiol.  Chetnie,  Bd.  XXIV.,  1898. 

8.  A    Contribution    to    the    Chemistry   of    Cytological    Staining. 

Aviej'ican  Journal  of  Physiology,  Vol.  I.,  1898. 

9.  The  Determining  Causes  of  Cell  Division.     New  York  Medical 

Journal,  1898. 
[o.   The  Life  and  Work  of  Felix  Hoppe-Seyler.     Popular  Science 
Monthly,  1898. 

[I.  Structural  Changes  in  the  Pancreas  Cell,  together  with  some 
General  Considerations  on  Cell  Metabolism.  Submitted  as  an 
Alternative  Thesis  to  Columbia  University  for  the  Degree  of 
Doctor  of  Philosophy.  To  appear  in  the  Journal  of  Mor- 
phology. 


[Annals  N.  Y.   Acad.  Sci.,  XL,  No.   14,  pp.  293  to  368,  September  12,  1898.] 


THE  PHYSIOLOGY  OF  SECRETION. 

Albert    Mathews. 

(Read   April    ii,    1898.) 

I.  Introduction  :                                          '  Page. 
Criticism  of  the  secretory  nerve  theory .   294 

II.  Sympathetic  Salivary  Secretion  :    .     . 303 

a.  The  rate  of  sympathetic  secretion 304 

/'.   The  decrease  in  amount  of  saUva  obtainable  upon  several  successive  stimu- 
lations        309 

c.  The  augmentation  of  sympathetic  saliva 311 

d.  Paralysis  of  the  sympathetic  by  emptying  the  ducts  and  its  restoral  to  power 

by  injection  of  fluid  into  the  ducts 314 

e.  The  character  of  sympathetic  saliva 320 

f.  Further  evidence  of  the  muscular  nature  of  the  mechanism  of  sympathetic 

secretion 324 

g.  The  location  and  nature  of  the  contractile  substance  in  the  gland  ....   328 

//.  Changes  in  the  gland  cells  on  sympathetic  stimulation 328 

?'.   Summaiy  and  conclusion 329 

III.  Other  Secretions  due  to  Muscle-Action  : 331 

IV.  Salivary  Secretion  Ensuing  on   Stimulation  of   the  Vaso-Dil.ator 

Nerves  : 

a.  The  increase  in  the  percentage  of  organic  constituents  coincident  with  an 

increased  rate  of  secretion 332 

b.  The  post-mortem  chorda  secretion 337 

c.  The  nature  of  the  action  of  atropine  and  pilocarpine 349 

d.  The  action  of  quinine  and  nicotine 355 

c.   Evidence  of  the  osmotic  character  of  the  salivary  secretions  which  are  ac- 
companied by  vaso-dilation 356 

f.   Conclusion.     The  physiology  of  salivary  secretion 358 

V.  Some  Other  Secretions  : 359 

a.  The  secretion  of  sweat 359 

b.  The  secretion  of  the  pancreas 360 

VI.  General  Conclusion  and  Summary  : 361 

VII.  Literature  : 364 

Annals  N.  Y.  Acad.  Sci.,  XI,  September  12,  1898 — 20. 

(293) 


294  MATHEWS. 

I.    INTRODUCTION. 

A  Criticism  of  the  Secretory-nerve  Theory. 

Nearly  fifty  years  ago  it  was  suggested  by  Ludwig*^  that  se- 
cretion was  a  function  of  the  gland  cells  controlled  by  the  ac- 
tivity of  special  nerve  fibres.  Upon  the  gland  cell,  thus  em- 
phasized as  the  prime  factor  in  secretion,  and  upon  its  relation 
to  nerve  action,  most  of  the  subsequent  study  of  the  physiology 
of  secretion  has  been  focussed.  This  study  has  unearthed  such 
evidences  of  the  truth  of  Ludwig's  hypothesis  that  to-day  few 
theories  of  physiology  rest  upon  a  foundation  apparently  firmer, 
or  are  more  widely  accepted,  than  the  hypothesis  of  secretory 
nerves.  Indeed,  the  recent  discovery,*"  by  means  of  the  Golgi 
and  Ehrlich  methylen-blue  methods,  of  the  remarkably  rich 
distribution  of  nerves  to  glands,  and  of  the  endings  of  these 
nerves  about  the  gland  cells,  has  seemed  the  final  convincing 
demonstration  of  the  truth  of  the  theory  which  so  many  years 
ago  foretold  their  existence. 

The  theory  of  secretory  nerves  did  not  long  remain  in  the 
simple  form  suggested  by  Ludwig,  for  it  soon  received,  at  the 
hands  of  Heidenhain,  a  more  complete  and  definite  shape. 
First  seriously  worked  out  by  him  in  1868^^  the  theory  Avas 
further  developed  in  1878^"  and  took  its  final  form  in  his  great 
treatise  on  secretion  embodied  in  Hermann's  Handbuch  der 
Physiologic  in  1880.^^  The  Ludwig-Heidenhain  theory,  thus 
crystallized  by  Heidenhain,  has  been  the  lens  through  which 
the  facts  of  secretion  accumulated  from  1868  to  the  present 
time,  have  been  viewed.  This  theory  may  be  briefly  stated  as 
follows  : 

Secretion  is  a  specific  function  of  the  gland  cells  controlled  by 
special  secretory  nerve  fibres,  acting  directly  upon  these  cells. 
There  are  two  kinds  of  these  nerve  fibres  :  trophic  fibres,  which 
render  the  cell  contents  soluble  ;  and  secretory  fibres,  which 
diminish  the  resistance  to  filtration  offered  by  the  lumen  end  of 
the  cell.  In  consequence  of  this  decreased  resistance,  the  con- 
tents of  the  cell,  which  are  under  high  endosmotic  pressure, 
escape  into  the  lumen.  At  the  same  time  the  cell  imbibes  liquid 
from  the  lymph  space. 


SECRETION  PHYSIOLOGY.  295 

Heideiihain,  R.  Ueber  secretorische  ziud  trophische  Drihennerven,  PJli'iger'' s 
Archv.  f.  d.  gesam.  Physiologie.  Bd.  XVII,  iSjS,  pp.  60  and  following :  "The 
cell  is  normally  under  high  endosmotic  pressure.  On  nerve  stimulation  a 
molecular  rearrangement  takes  place  at  the  lumen  end  of  the  cell,  so  that  the  re- 
sistance to  filtration  is  diminished  and  water  flows  out.  This  flow  may  be  hastened 
by  contractions  of  the  protoplasm,  as  Klihne  observed  in  the  rabbit's  pancreas  under 
the  microscope.  The  tension  of  the  water  within  the  cell  being  thus  diminished, 
water  begins  to  flow  out  of  the  lymph  and  capillaries  into  the  cell.  At  the  end  of 
stimulation  molecules  are  rearranged,  the  loss  of  water  by  the  cell  ceases,  and  se- 
cretion stops."  "  The  attractive  pull  on  the  water  comes  from  the  protoplasm  of 
the  outer  zone." 

Before  proceeding  with  the  discussion  of  the  evidence  upon 
which  this  theory  rests,  it  will  make  the  matter  clearer  to  recall 
the  conception  of  secretion  which  the  Ludwig-Heidenhain 
theory  supplanted.  For  some  of  the  facts  brought  forward  by 
these  authors  are  of  value,  not  as  direct  evidence  of  the  exist- 
ence of  secretory  nerves,  but  because  they  disprove  an  alterna- 
tive earlier  conception.  The  prevalent  conception  of  secretion, 
before  Ludwig's  time,  was  that  liquid  driven  by  intra-capil- 
lary  pressure  filtered  out  through  the  gland. ^'^  The  chorda 
tympani  was  the  principal  secretory  nerve  then  known,  and  it 
was  believed  to  cause  secretion  by  greatly  increasing  intra-ca- 
pillary  pressure  by  contraction  of  the  veins  or  arterioles.  The 
discovery  of  the  vaso-dilator  function  of  this  nerve  shortly 
thereafter  by  Claude  Bernard  re-emphasized  the  possibility  of 
a  high  intra-capillary  pressure  being  an  essential  cause  of  secre- 
tion. It  is  not  surprising  that  many  physiologists  of  that  day 
believed  that  this  striking  correspondence  between  vaso-dilation 
and  secretion  could  not  be  accidental,  and  it  was  natural  for 
them  to  refer  the  secretory  power  of  the  nerve  to  its  action  on 
the  blood  vessels. 

The  first  blows  against  the  theory  that  the  vascular  system 
stood  necessarily  in  a  causal  relation  to  secretion  were  dealt  by 
Ludwig  and  his  pupils.  They  discovered  that  stimulation  of  the 
upper  end  of  the  cut  cervical  sympathetic  nerve  caused  a  secretion 
from  the  submaxillary  gland  of  the  dog,^'^  but  this  secretion,  un- 
like that  due  to  the  chorda,  was  afterwards  found  to  be  accom- 
panied by  a  pronounced  vaso-constriction  instead  of  dilation. 
They  found  that  the  pressure  capable  of  being  generated  by  the 
saliva  flowing  from  Wharton's  duct  might  considerably  surpass 


296  MATHEWS. 

the  pressure  of  the  blood  even  in  the  carotid  artery.  They 
thus  demohshed,  once  and  for  all,  the  filtration  theory.  They 
found,  further,  that  the  temperature  of  the  sahva  secreted  from 
the  dog's  submaxillary  might  surpass  by  i.5°C.,  the  temperature 
of  the  blood  in  the  carotid  artery,"*^  and  as  final  evidence  that  the 
chorda  tympani  could  induce  secretion  independent  of  the  vaso- 
motor action,  they  brought  forward  the  observation  that  stimu- 
lation of  this  nerve  still  caused  a  secretion,  some  minutes  after 
the  heart  ceased  to  beat.^^  It  is  not  strange  that,  in  the  face  of 
such  facts,  Ludwig  should  have  felt  compelled  to  assume  the 
secretory  activity  of  the  gland  cell. 

Heidenhain  soon  added  other  facts  pointing  in  the  same  di- 
rection. He  found  that  if  the  blood  supply  be  cut  off  from  the 
submaxillary  gland  by  compression  of  the  artery  the  chorda 
still  caused  a  secretion  analogous  to  the  post-mortem  secretion 
after  the  heart  ceases  to  beat.'^  Giannuzzi^^  discovered  that  by 
the  injection  of  sodium  carbonate  or  a  dilute  solution  of  hydro- 
chloric acid  into  Wharton's  duct  a  pronounced  vaso-dilation  en- 
sued, on  stimulation  of  tKe  chorda,  but  no  secretion.  Heiden- 
hain^^ found  that  quinine  sulphate  injected  into  the  duct  had  a 
similar  action,  and  that  atropine"^  effectually  paralyzed  secretion, 
while  leaving  the  vaso-dilator  power  of  the  nerve  unaltered. 
Heidenhain^"  also  discovered,  and  Langley  confirmed  his  obser- 
vation, that  after  the  chorda  tympani  had  been  paralyzed  by  the 
action  of  nicotine,  either  injected  subcutaneously  or  applied  di- 
rectly to  the  submaxillary  ganglion,  the  chorda  tympani  recov- 
ered its  secretory  function  before  its  dilator  function.  He 
observed,  also,  that  after  the  chorda  had  been  cut  and  allowed 
to  degenerate  for  2-3  days  stimulation  of  the  nerve  still  caused 
an  increase  in  secretion,  without  an  increase  in  the  flow  of  blood 
from  the  gland's  vein.  This  evidence  showed  that  vaso-dilation 
might  ensue  without  a  secretion,  that  secretion  might  take 
place  unaccompanied  by  vaso-dilation,  and  that  secretion  might 
be  caused  by  stimulating  dilator  nerves  after  cutting  off  the 
blood  supply.  If  these  facts  were  true  vaso-dilation  could  not 
be  the  cause  of  secretion,  and  hence  that  cause  must  be  sought 
in  some  other  gland  element  than  the  blood  vessels. 


SECRETION  PHYSIOLOGY.  297 

Evidence  of  a  more  positive  kind  of  the  direct  action  of  nerves 
upon  the  gland  cells  was  not  long  lacking.  Heidenhain  showed 
that  stimulation  of  secretory  nerves  caused  well-marked  changes 
in  the  structure  of  the  gland  cells.-'  He  discovered  that  the 
specific  constituents  of  the  secretion  were  accumulated  in  the  cell 
during  glandular  rest,  and  discharged  from  the  cell  during  secre- 
tion. That  these  substances  were  not  simply  dissolved  from  the 
cells  by  the  water  stream  passing  through  them  he  endeavored 
to  show  by  the  fact  that  on  passing  from  a  weak  to  a  stronger 
stimulation  of  the  chorda  tympani,  or  other  dilator  secretory 
nerve,  not  only  the  rate,  but  also  the  concentration  of  the  secre- 
tion increased.  Apparently  the  more  rapidly  secreted  saliva, 
although  in  contact  with  the  cell  contents  for  a  briefer  time,  never- 
theless dissolved  more  of  them  than  that  more  slowly  secreted. 
This  obviously  would  have  been  impossible  if  the  contents  of  the 
cell  had  not  been  rendered  more  soluble  by  the  action  of  the 
nerve  during  the  stronger  stimulus.  He  brought  forward,  also, 
still  more  convincing  evidence. ^^  In  the  dog's  parotid  gland 
stimulation  of  the  cervical  sympathetic  causes,  generally,  no 
secretion,  but  if  this  nerve  be  irritated  coincident  with  the  dila- 
tor secretory  nerve  the  saliva  secreted  under  the  influence  of 
both  nerves  is  more  concentrated  than  that  secreted  during  irri- 
tation of  the  dilator  nerve  alone.  Apparently  the  sympathetic, 
though  causing  no  secretion,  must,  nevertheless,  act  on  the  cells, 
so  as  to  render  their  contents  more  soluble.  That  this  effect  of 
the  sympathetic  could  not  be  due  to  any  possible  action  of  the 
nerve  on  contractile  tissue  of  the  gland,  as  suggested  by  Schiff,'^'' 
Eckhard^'^  and  others,  Heidenhain  believed  von  Wittich"  had 
conclusively  demonstrated.  That  the  well-known  high  concen- 
tration of  the  sympathetic  saliva  could  not  be  referred  to  the 
nerve's  vaso-constrictor  action  Heidenhain^-  showed  by  the 
fact  that,  if  the  gland  artery  be  almost  totally  compressed,  the 
following  chorda  saliva  was  not  rendered  more  concentrated. 

These  facts  undoubtedly  furnish  strong  evidence  that  the 
sympathetic  and  other  nerves  act  on  the  gland  cells,  not  only 
increasing  the  flow  of  water  through  them,  but  also  rendering 
their  contents  more  soluble. 


298  MATHEWS. 

Most  of  these  facts,  brought  out  chiefly  in  the  saHvary  glands, 
have  been  found  to  be  true  for  other  glands.  The  independ- 
ence of  blood  pressure  and  secretion,  the  inhibitory  action  of 
\  atropine,  and  an  increase  in  concentration  of  the  secretion  coinci- 
'dent  with  a  more  rapid  flow,  have  been  observed  by  Afanassiew 
arid  Pawlow,^  Gottlieb, ^^  Pawlow  and  S.^^Simonoskajain-the  pan- 
creas, stomach  and  other  glands,  in  which  secretion  is  normally 
accompanied  by  vaso-dilation.  Sweat  may  be  secreted  during 
vaso-constriction  or  vaso-dilation,  and  in  the  cat's  foot,  twenty 
minutes  after  ligaturing  the  artery  or  cutting  the  leg  from  the 
body/"  The  skin  glands  of  amphibia  can  secrete  in  the  total 
absence  of  blood  supply.'^  Moreover,  of  recent  years,  the  im- 
portance of  the  condition  of  the  secreting  cells,  as  a  factor  of 
secretion,  has  been  clearly  realized.  The  quick  paralysis  of 
some  secretions  during  dyspnoea  or  by  the  action  of  drugs  has 
emphasized  this  factor  of  secretion.  .  Even  in  the  kidney,  where 
secretion  apparently  more  nearly  approaches  a  filtration,  it  has 
been  shown  that  the  condition  of  the  capillary,  or  glomerular 
epithelium,  and  the  character  of  the  blood,  exerts  an  influence 
on  the  secretion.^  The  possibility  at  once  suggests  itself  that 
if  the  condition  of  the  cells  is  so  readily  affected  by  external 
agents  it  maybe  modified  by  direct  nerve  action.  The  very 
rich  nerve  supply  of  many  glands  and  the  intimate  association 
of  nerve  end  and  gland-cell  undoubtedly  bring  strong  confirma- 
tion to  this  supposition. 

From  this  brief  outline  the  extreme  complexity  of  the  problem 
of  secretion  will  be  manifest.  Some  secretions  are  accompanied 
by  vaso-dilation  ;  others  by  vaso-constriction.  Some  may  per- 
sist twenty  minutes  after  cutting  off  the  blood  supply  ;  others 
are  paralyzed  within  two  or  three  minutes.  Some  are  paralyzed 
by  atropine  and  quinine  ;  others  are  not.  In  the  same  gland 
stimulation  of  one  nerve  may  cause  the  secretion  of  a  large 
amount  of  watery  secretion,  while  stimulation  of  another  nerve 
causes  the  secretion  of  a  small  amount  of  exceedingly  viscid 
secretion.  There  seems,  in  fact,  to  be  no  general  rule  of  secre- 
tion true  for  all  glands.  The  great  difference  between  the  phe- 
nomena of  different  secretions  suggests  that  the  mechanisms  of 


SECRETION  PHYSIOLOGY.  299 

those  secretions  may  be  different  in  different  cases.  However 
probable  it  may  seem,  a  priori,  that  there  is  everywhere  one 
fundamental  mechanism  underlying  all  these  secretions,  a  de- 
cent regard  for  truth  forbids  one  accepting  so  far  reaching  a  con- 
clusion, unless  it  be  supported  by  very  strong  evidence. 

In  the  present  paper,  therefore,  I  wish  to  reopen  the  question 
whether  all  secretions  are  due  to  the  activity  of  the  gland  cells, 
and  to  re-examine  the  evidence  of  the  existence  of  nerves  act- 
ing on  those  cells.  The  great  theoretical  and  practical  im- 
portance of  Ludwig's  conception  is  a  sufficient  excuse  for  a 
critical  and  experimental  review,  in  the  light  of  the  physiology 
of  the  present  day,  of  the  evidence  upon  which  that  theory  rests. 
Since  the  publication  of  Ludwig's  and  Heidenhain's  Avork  on  se- 
cretion knowledge  has  been  acquired  of  vaso-motor  changes, 
osmosis,  lymph  formation  as  well  as  secretion  proper,  which 
might,  possibly,  cause  even  Heidenhain  or  Ludwig,  if  consider- 
ing the  subject  at  this  time,  to  adopt  a  somewhat  different 
interpretation  of  much  of  this  evidence  from  that  heretofore  pro- 
posed. Such  a  review  seems  the  more  necessary  for  the  reason 
that  special  applications  of  the  theory  have  been,  from  time  to 
time,  questioned,  and  because,  as  will  be  apparent  in  the  course 
of  the  following  discussion,  some  of  Heidenhain's  inferences  are 
unsound,  owing  to  his  having  neglected  to  consider  possibilities 
now  known  to  be  of  importance.  His  recent  extension  of  the 
theory  to  lymph  formation,  for  example,  has  been  seriously  dis- 
puted by  Starling,*^^  Cohnheim  and  others.  Starling  especially 
has  shown  the  uselessness  of  assuming  any  such  secretory 
mechanism  in  certain  special  cases,  and  has  thus  thrown  doubt 
upon  the  truth  of  the  theory  as  a  whole.  Langley^'  has  ques- 
tioned the  necessity  for  assuming  distinct  "trophic"  fibres  to 
explain  salivary  secretion,  and  for  the  kidney  secretion  special 
inferences  of  Heidenhain  have  been  challenged  by  Senator, 
Adami^  and  v.  Sobiranski.^''  The  difference  in  pressure  be- 
tween blood  and  secretion  observed  by  Ludwig  may  be  readily 
accounted  for  on  the  basis  of  osmosis  quite  apart  from  any  cell- 
activity.^^  "The  difference  in  temperature  between  saliva  and 
blood  has  been  denied  by  Bayliss  and  Hill,'^  working  with   bet- 


300  MATHEWS. 

ter  methods.  For  some  of  the  facts,  also,  errors  of  method 
greatly  diminish  the  value  of  the  testimony  they  offer,  and 
some  of  that  evidence  depends  upon  the  assumption  that  all  se- 
cretions are  probably  due  to  the  same  cause.  Hence,  whether 
the  theory  of  secretory  nerves  is  true  or  not,  it  must  be  admit- 
ted, I  believe,  that  little  of  the  evidence  which  has  hitherto  been 
presented  in  support  of  that  hypothesis  can  be  accepted  as  it 
stands. 

While  fully  aware,  therefore,  of  the  strong  a  priori  probability 
that  nerves  may  act  on  gland  cells  so  as  to  affect  osmosis  through 
them,  and  while  appreciating  the  strength  of  the  evidence  that 
they  do  so  act,  I  feel  myself  compelled,  for  the  reasons  presented 
in  the  following  criticisms  of  that  evidence,  to  question  whether 
secretion  is  really'  controlled  in  this  manner. 

But  not  only  is  the  evidence  upon  which  the  secretory  nerve 
theory  rests  inconclusive;  there  are  also  certain  weaknesses  in  the 
theory  itself  which  deserve  more  attention  than  they  have 
hitherto  received.  It  is  by  no  means  easy  to  understand  how 
the  nerve  can  affect  the  cell  in  such  a  way  as  to  cause  a  secre- 
tion. The  mere  discharge  of  liquid  from  the  cells  into  the  gland 
lumen  would,  as  pointed  out  elsewhere,  lead  to  no  secretion 
from  the  gland  ducts.  To  obviate  this  difficulty  Heidenhain 
supposed  that,  while  the  secretory  nerve  diminished  the  resist- 
ance of  the  inner  end  of  the  cell,  the  outer  zone  imbibed  water 
from  the  lymph  and  capillary.  The  outer  zone  exerted  an  at- 
tractive pull  upon  the  lymph.  By  the  imbibition  of  this  lymph 
the  secretion  was  forced  along  the  ducts.  This  explanation  leads 
at  once  to  difficulties.  Not  only  is  the  explanation  exceedingly 
hypothetical,  but  it  is  difficult  to  see  why,  if  the  pull  on  the  lymph 
comes  from  the  outer  zone,  secretion  should  be  slowest  after 
long  stimulation,  or  during  paralytic  secretion,  when  the  outer 
zone  is  at  its  greatest  development,  and  how  secretion  can  take 
place  at  all,  or  with  any  rapidity,  in  glands  in  which  the  outer 
zone  has  almost,  or  completely,  disappeared,  as  in  mucous  sal- 
ivary glands,  the  stomach  or  pancreas,  after  a  long  rest.  It  is 
also  difficult  to  understand  sympathetic  secretion,  which  takes 
place  during  a  period  of  vascular  constriction.      Nor  can  we  ig- 


SECRETION  PHYSIOLOGY.  301 

nore  the  extreme  complexity  of  the  theory.  The  assumption 
that  each,  or  any,  cell  of  the  sub-maxillary  gland  has  acting 
upon  it  four  totally  different  nerve  ends  is,  in  itself,  highly  im- 
probable. A  further  difficulty  is  encountered  when  we  critically 
examine  Heidenhain's  assumption  that  the  trophic  and  secretory 
fibres  are  unequally  distributed  to  the  chorda  tympani  and  sym- 
pathetic. It  seems  simple  enough  to  refer  the  small  secretion 
ensuing  on  sympathetic  stimulation  to  the  presence  of  a  small 
number  of  secretory  fibres  in  this  nerve,  but  if  it  be  asked 
whether  these  fibres  innervate  all  the  cells,  or  only  a  portion  of 
them,  we  are  at  once  plunged  into  a  maze  from  which  there  is 
no  way  out.  If  they  innervate  all  the  cells  we  may  ask  why, 
if  a  few  fibres  suffice,  more  should  be  present  in  the  chorda, 
and  why  the  secretion  should  not  be  as  copious  as  the  chorda's. 
If  they  innervate  a  part  of  the  cells  only,  new  assumptions  must 
be  made  to  understand  why  stimulation  of  the  sympathetic 
should  exhaust  the  constituents  of  the  whole  gland.  If  we 
abandon  the  trophic  fibres  and  postulate  one  sort  of  fibre  only, 
the  secretory,  acting  on  the  cell,  Heidenhain's  facts  become 
largely  inexplicable.  Furthermore,  when  Heidenhain^'^  assumed 
secretory  nerves  to  the  capillaries  he  undermined  much  of  the 
evidence  accumulated  by  him  of  secretory  nerves  to  glands.  For 
many  of  the  facts  of  gland  physiology  might  be  understood  by 
reference  to  these  capillary  nerves.  Atropine,  for  instance,  might 
conceivably  prevent  secretion  by  paralyzing  the  ends  of  the  se- 
cretory nerves  of  the  capillaries,  thus  inhibiting  the  production 
of  lymph  and  fluid  necessary  for  secretion. 

In  the  present  paper  I  have  considered  chiefly  the  physiology 
of  secretion  in  the  salivary  glands.  The  experimental  work  has 
been  devoted  chiefly  to  studying  the  exceptional  features  of  that 
secretion  which  have  seemed  difficult  of  comprehension  on 
any  other  than  the  cellular  theory  of  secretion.  I  have  ven- 
tured, however,  to  bring  some  other  secretions  into  relation 
with  the  conclusions  concerning  the  mechanisms  of  salivary 
secretion. 


302  MATHEWS. 

It  may  prevent  confusion  and  reconcile  what  might  appear  to 
be  contradictory  statements,  to  give  here  the  chief  conclusion 
drawn  in  the  present  paper.  This  is,  that  there  is  no  single 
mechanism  of  secretion.  In  some  glands  the  stored  metabolic 
products  are  driven  out  of  the  cells  by  the  action  of  muscle,  as 
in  Amphibian  skin  glands  and  sudoriferous  glands  ;  in  others 
they  are  removed  by  currents  of  lymph,  which  are  probably  the 
result  of  osmosis,  as  in  the  pancreas,  stomach,  salivary  glands  ; 
in  some  cases  the  cells  imbibe  water  until  they  burst,  and  their 
contents  rush  into  the  gland-lumen,  as  in  the  intestinal  cells  of 
Ptychoptera  larvae  ;  in  others  the  inner  end  of  the  cell  crumbles 
to  pieces,  as  in  the  mammalian  milk  glands.  Two,  or  more,  of 
these  mechanisms  may  coexist  in  one  gland,  and  it  is  this  which 
has  rendered  the  physiology  of  such  glands  as  the  salivary  so 
confusing.  In  the  submaxillary  gland,  for  example,  I  believe 
we  have  a  muscular  mechanism,  innervated  by  the  sympathetic  ; 
and  an  osmotic  mechanism,  innervated  by  the  chorda.  The 
sympathetic,  in  other  words,  causes  secretion  as  Eckhard,^^ 
Schiff,*  ^'  and  others^"  have  maintained,  by  its  action  on  contrac- 
tile tissue  in  the  gland  body,  thus  mechanically  compressing  the 
ducts  and  alveoli  and  squeezing  out  the  secretion.  The  chorda 
probably  causes  secretion,  by  its  dilator  action  on  the  blood  ves- 
sels. The  following  pages  present  the  evidence  for  these  con- 
clusions. 

Before  proceeding  farther  it  is  necessary  to  define  the  sense 
in  which  the  word  "secretion"  is  here  used.  At  present  the 
word  has  no  very  definite  significance,  as  it  refers  to  different 
processes.  For  the  sake  of  clearness  it  would  be  better  to 
designate  these  various  processes  by  different  names.  I  suggest 
that,  in  the  future,  the  word  secretion  be  used  to  indicate  the 
process  of  extruding  subtances  from  cells  into  the  lumen  of  the 
gland,  the  process  of  expulsion  from  the  ducts,  and  the  substances 
secreted  by  the  gland.  By  this  use  of  the  word  cellular  secre- 
tion will  be  generally  coincident  in  time  with  glandular.     For  the 

*Schifif,  loc.  cit.,  p.  304,  I.  "  It  is  probable  that  the  great  sympathetic  which 
causes  constriction  of  the  parotid  vessels  causes,  at  the  same  time,  the  tissue  of  the 
gland  to  contract,  and  that  by  this  contraction  the  gland  empties  itself  of  its  con- 
tents formed  independent  of  nerve  action." 


SECRETION  PHYSIOLOGY.  303 

process  of  the  formation  of  substance  by  the  gland  cell — a  dif- 
ferent process,  but  one  at  present  included  under  secretion — I 
propose  the  name  "  Hylogenesis  "  (Gr.  bhj  matter  and  yivtatz 
generation),  and  for  the  substances  formed  the  name  "  Hylogens." 
Thus  trypinogen,  mucinogen,  pepsinogen  are  hylogens.  The 
secretions  consist  of  the  hylogens  plus  water,  salts  and  other 
substances  derived  unchanged  from  the  blood.  The  present 
paper  deals  solely  with  secretion  proper.  Hylogenesis  is  con- 
sidered elsewhere.*  This  word  seems  to  me  preferable  to  that 
of  "  Mesastates,"  suggested  by  Mr.  J.  N.  Langley.  Ranvier''^ 
and  Van  Gehuchten^'^  wish  to  call  the  process  here  named  hylo- 
genesis, "  secretion."  This  seems  to  me  inadvisable,  as  thereby 
cellular  secretion  would  correspond  with  glandular  rest. 

The  experimental  work  embodied  in  this  paper  has  been 
carried  on  chiefly  in  the  Physiological  Laboratory  of  Columbia 
University,  and  I  am  particularly  indebted  to  Professor  Curtis 
and  Professor  Lee  both  for  extending  to  me  facilities  of  the 
laboratories  and  for  suggestive  criticism.  A  portion  of  the 
work  was  done  in  the  physiological  laboratories  of  Cam- 
bridge University,  England,  and  Marburg  University,  Germany. 
I  desire  to  express  my  hearty  appreciation  of  the  courtesy  of 
Professor  Michael  Foster  and  Professor  Kossel  in  placing  the 
facilities  of  their  laboratories  at  my  disposal.  To  Mr.  J.  N. 
Langley  I  am  indebted  for  critical  suggestions. 

IL  SYMPATHETIC    SALIVARY  SECRETION. 

Stimulation  of  the  upper  end  of  the  divided  cervical  sympa- 
thetic nerve  of  the  cat,  horse,  dog,  sheep  or  rabbit  generally  causes 
a  secretion  from  the  salivary  glands.  This  secretion  has  every- 
wheref  the  same  characteristic  features,  indicating  that  it  is  pro- 
duced in  all  salivary  glands  in  the  same  manner.  These  com- 
mon features  are  the  following  :  The  saliva  reaches  its  maximum 
rate  of  flow  in  the  first  lo  or  20  seconds,  and  then  generally 
ceases,  although  stimulation  lasts  for  several  minutes.      If  sev- 

*  Shortly  to  appear  in  the  Jonr)ial  of  MorpJwlogy. 

I  Except  in  the  resting  parotid  and  submaxillary  glands  of  the  dog.  See  next 
page. 


304  MATHEWS. 

eral  stimulations  follow  closely,  one  upon  the  other,  the  amount 
of  saliva  secreted  at  each  stimulation  rapidly  diminishes  and 
often  becomes  nothing.  Stimulation  becomes  then  again  effec- 
tive if  the  gland  be  allowed  to  rest,  if  the  chorda  be  irritated,  or 
if  liquid  be  injected  into  the  gland  duct.  Finally,  sympathetic 
secretion  is  invariably  accompanied  by  vascular  constriction,  and 
the  saliva,  with  the  doubtful  exception  of  that  of  the  cat,^^  con  - 
tains  more  organic  matter  than  that  secreted  from  the  same 
gland  under  the  influence  of  the  dilator  nerve. 

That  there  are  deviations  from  the  typical  course  of  a  sympathetic  secretion  just 
sketched  need  hardly  be  said.  Such  deviations  are  probably  due  (seep.  309)  to 
the  changing  fluidity  of  the  saliva.  When  the  saliva  is  thin,  as  in  the  horse,  rabbit,  cat 
or  sheep,  the  secretion  follows  a  very  typical  course  ;  if  the  saliva  be  viscous,  as  in 
the  resting  salivary  glands  of  the  dog,  the  latent  period  is  longer,  and  the  secretion 
persists  longer.  These  variations  shed  a  not  unimportant  light  on  the  mechanism 
of  secretion. 

To  explain  these  typical  phenomena,  assuming  the  secretory 
activity  of  the  gland  cell,  Heidenhain  supposed  that  the  sympa- 
thetic nerve  carried  three  kinds  of  fibres  :  trophic,  secretory  and 
vaso-constrictor.  The  trophic  fibres  converted  large  quantities 
of  mucinogen  (submaxillary)  into  soluble  mucin,  making  the 
juice  rich  in  organic  bodies  ;  the  secretory  fibres  caused  secretion  ; 
the  constrictor  neutralized  the  secretory  action  and  stopped 
secretion.  The  quick  failure  of  the  nerve  on  successive  stimu- 
lations was  referred  to  the  exhaustion  of  nerve,  nerve  end,  or 
gland  cell. 

The  general  features  of  syiupatlietic  secretion  seem  to  me,  hozo- 
ever.^  plainly  to  suggest  that  the  secretion  has  been  driven  from  the 
gland  by  a  compression  of  the  ducts  and  alveoli  by  some  contractile 
tissue.  I  wish  to  consider  these  features  separately,  from  this 
point  of  view,  together  with  experiments  bearing  on  their  proper 
interpretation. 

a.  The  Rate  of  Sympathetic  Secretion. 

Experiments  I.   and  II. 

Cat  and  dog.  Submaxillary.  Animals  under  ether.  Canula 
in  Wharton's  duct,  connected  with  a  narrow  tube  graduated  in 
millimeters,  250  mm.  =  0.82  cc.      Reading's  every  ten  seconds 


SECRETION  PHYSIOLOGY.  305 

in  mm.  Chorda-lingual  divided  in  each  case.  Cervical  sympa- 
thetic divided  and  stimulated  by  tetanic  shocks,  secondary  coil 
180-100  mm.  The  chorda  was  first  stimulated  intermittently 
for  an  hour,  so  that  the  glands  were  secreting  watery  saliva. 

Cat.  Dog. 

I         II        in  I  II 

1st  10  seconds  of  sympathetic  stimulation  ...  10  ..  9  10  ...  25  ..  17 

2d     "       "       "  "  "  .    .    .    9  .    .  5  .    .     6  .    .    .    4  .    .     2 

3d     "       "       "  "  "  .    .    .    o  .    .  o  .    .     o  .    .    .     3  .    .     2 

4th    "       "       "  "  "  ...0..0..0.        .2..     I 

5th    "       "       "  "  "  ...0..0..0...2..2 

off      off  off 

6th    "       "        "  "  "  ,    .    ,     o  .    ,  o  .    .    o  .    .    .     8  .    .     I 

off  off 

By  inspection  of  these  figures,  It  is  seen  that  on  stimulation 
the  secretion  comes  suddenly,  reaches  its  maximum  rate  of  flow 
in  the  first  few  seconds,  and  then  quickly  subsides.  In  the  cat, 
it  abruptly  ceases  after  20  seconds.  In  the  dog,  probably  owing 
to  the  greater  viscidity  of  the  saliva  and  the  resistance  offered  to 
its  passage  by  the  fine  gland-tubules,  it  persists  slightly  through- 
out the  stimulation. 

Heidenhain  attributes  the  abrupt  cessation  of  secretion,  after 
a  few  seconds,  to  the  vaso-constrictor  action  of  the  nerve,  in 
consequence  of  which  the  secretory  mechanism  is,  as  it  were, 
suffocated."^  That  this  explanation  is  incorrect  may  readily  be 
shown  by  cutting  off  the  blood  by  compressing  the  gland's 
artery,  or  by  decapitation.  In  such  cases,  as  the  following  ex- 
periments show,  a  perfectly  typical  secretion  may  ensue  on 
stimulation  of  the  sympathetic,  ten  or  more  minutes  after  Hga- 
turing  the  artery,  or  decapitation. 

Experiment  Va. 

(A  full  account  of  this  experiment  is  given  on  page  343.) 
Large  dog,  which  had  received  3CC.  i  %  morphine  sulphate 
subcutaneously.  Ether  given  through  tracheal  tube.  Sub- 
maxillary dissected  free,  and  remained  attached  only  at  the 
hilus  and  by  its  veins.  Chorda-lingual  and  sympathetic  cut. 
Canula  connected  with  tube  graduated  in  millimeters  in  Whar- 
ton's duct.  Gland's  artery  exposed  by  extirpation  of  the 
digastric  muscle.     Tetanic  shocks.     Secondary  coil  at  150.     The 


306 


MATHEWS. 


secretion  of  the  sympathetic  is  given  in  mm.  at  ten  second  in- 
tervals, 250  mm.  =  0.82.  cc. 


25 


3     25 


3 

30 

3 

32 

3 

35 

3 

37 

3 

40 

3     42 


Time. 
h 


3     30 


4 

C7 

30 

4 

07 

30 

-    4 

08 

4 

08 

-    4 

09 

4 

09 

-    4 

II 

4 

12 

-    4 

13 

4 

13 

-    4 

14 

4 

15 

-   4 

17 

4 

17 

30 

-    4 

18 

4 

20 

4 

25 

4 

26 

-    4 

27 

4 

29 

30 

4 

45 

30 

4 

46 

30  - 

-   4 

47 

4 

•48 

30   - 

-    4 

49 

4 

50 

- 

-    4 

51 

4 

51 

30   - 

-    4 

52 

4 

53 

4 

53 

- 

-    4 

54 

4 

54 

- 

-   4 

55 

4 

55 

30  - 

-    4 

56 

4 

57 

- 

-    4 

58 

5 

02 

5 

03 

- 

-    5 

09 

5 

09 

- 

-    5 

10 

Nerve  Stimulated. 

The  artery  going  to  the  gland 
was  clamped  close   to   the 

hilus. 

Chorda  (intermittent 


Secretion. 


30 


15 


39 


Sympathetic 


Copious  at  first,  it  gradually 
ceases. 


16,  3,  2,  2,  0,  0,  off. 

O,  O,  O,  I,  o,  o,  off. 

o,  o,  o,  o,  o,  o,  off. 


Interval  (see  page  317). 
Artery  undamped.      Chorda 
stimulated  intermittently  for 
several  minutes. 

Artery  clamped. 

Chorda  155 

"  (10  sec.  int. )   30 

16 


Sympathetic. 

Chorda 
Sympathetic. 

Interval  (see  page  317). 
Sympathetic. 
Chorda.  , 
Interval  (see  page  317). 
Artery       undamped.        The 
gland   secretes     spontane- 
ously.     Chorda  stimulated 
intermittently. 

Artery  clamped. 


n,  4, 2, 2, 0,  off. 

o 
10,  4,  0,  0. 

o,  o,  o. 

o,  o,  o. 


Chorda 

175 

" 

30 

" 

10 

(< 

2 

0 

Sympathetic 

8,  2,  1,  0. 

Chorda 

0,  0,  0,  0. 

Sympathetic 

0 

0,  4,  3,  0,  0. 

Artery  undamped. 

Spontaneous  secretion. 

Sympathetic. 

9,  3,  2,  6,  0. 

SECRE  TION  PHYSIOL  OGV. 


307 


Experiment  V. 

Large  dog  under  morphine  and  chloroform.  Right  submax- 
illary gland  prepared.  Chorda  lingual  and  sympathetic  cut. 
Each  nerve  causes  a  good  secretion.  Readings  as  in  previous 
experiments.  Canula  in  Wharton's  duct.  Secondary  coil  150. 
Tetanic  shocks. 


h.     m.      s. 
5      49     30 


5 

50 

30 

5 

55 

5 
5 

57 
58 

6 

10 

55 


-   6 


NERVE    STIMULATED. 

Head  cut  oft' as  rapidly  as  possible. 
Spinal  cord   and  vertebral  column 
not  severed. 
Chorda  (intennittent) 

"       (coil  70) 
Sympathetic  (coil  7) 
No  stimulation. 
Sympathetic 


SECRETION. 
175 

o 
40,  20,  6,  2,  0. 

%    5,  2,  0,  0. 


TIME. 

m. 

S. 

h. 

m. 

4 

30 

!i 

40 

-  4 

35 

4 

35 

-  4 

38 

4 

38 

Experiment  VI. 

Dog.  Conditions  of  experiment  the  same  as  in  Experiment 
V.      Submaxillary.      Both  nerves  active. 

NERVE.  SALIVA    SECRETED  IN  MM. 

Head  completely  severed  from  body. 

Chorda  intermittent  65 

Chorda.  o 

Sympathetic.  14,  3,  2,  2,  0. 

The  foregoing  experiments,  demonstrating  that  a  sympathetic 
secretion  may  be-  obtained  ten  minutes  after  all  fluid  and  oxygen 
have  been  cut  off  from  the  gland  shows,  I  think,  that  Heidenhain 
was  wrong  in  ascribing  the  quick  normal  cessation  of  secretion 
during  sympathetic  stimulation  to  the  nerve's  action  on  the 
blood  vessels.  It  is  obvious  that  vascular  constriction  can  have 
nothing  to  do  with  such  cessation,  because  the  changes  produced 
in  a  normal  gland  by  vascular  constriction,  namely,  diminution 
of  water  and  oxygen,  have  existed  in  all  three  experiments  at 
least  seven  minutes  before  the  nerve  was  stimulated,  and  con- 
tinue during  that  stimulation  without  in  any  way  affecting  the 
course  of  the  secretion. 

Even  a  normal  gland  secreting  a  very  viscous  saliva  furnishes 
evidence  against  the  truth  of  Heidenhain's  explanation.      In  the 


308  MATHEWS. 

resting  submaxillary  of  the  dog  the  sympathetic  secretion  may 
have  a  latent  period  of  many  seconds  and  persist  for  minutes. 
An  instance  of  such  a  kind  is  the  following  : 

Experiment  III. 

Large  morphinized  dog,  receiving  chloroform.  Both  chorda 
lingual  and  sympathetic  cut.  The  submaxillary  has  not  pre- 
viously been  secreting.  Sympathetic  stimulated  by  tetanic 
shocks.  Secondary  coil  15.  Readings  every  10  seconds  in 
millimeters  as  before.  The  saliva  was  extraordinarily  viscid. 
Total  stimulation  2  minutes,  40  seconds.  Latent  period  ^5 
seconds. 

Amount  of  secretion  :  o,  o,  o,  o,  5,  7,  7,  5,  5,  5,  4,  5,  5,  4,4, 
3  ;  off,  3,  I,  o. 

If  secretion  can  begin  after  42  seconds,  and  endure  for  two 
minutes,  during  a  period  of  vascular  constriction,  as  was  the 
case  in  this  experiment,  it  can  hardly  be  assumed  that  vaso- 
constriction is  the  cause  of  the  normal  failure  of  that  secretion 
within  twenty  seconds. 

Heidenhain  seems  to  have  overlooked  the  fact  that  a  sympa- 
thetic secretion  may  be  obtained  after  cutting  off  the  blood 
supply,  at  least  five  minutes  after  the  chorda  becomes  inopera- 
tive. He  referred  the  quick  loss  of  the  chorda's  power  in  these 
experiments,  to  the  suffocation  of  the  gland  cell.*  If  the  loss 
of  the  chorda's  secretory  power  is  due  to  the  paralysis  of  the 
gland  cell  by  suffocation,  the  sympathetic  must  cause  secretion 
in  some  other  way  than  action  on  the  cell,  since  this  nerve  causes 
a  normal  secretion  long  after  the  chorda  has  been  paralyzed. 

The  quick  gush  of  saliva  and  its  abrupt  cessation,  as  well  as 
the  anomalous  cases  represented  by  Experiment  III,  clearly  indi- 
cate a  muscular  mechanism  of  secretion.  They  are  probably  to 
be  explained  as  follows  :    On  sympathetic  stimulation  the  ducts 

*  Heidenhain,  R.  Hermann's  Handbuch  der  Physiologic  V,  p.  46:  "Die 
Ursache  der  Verlangsamung  der  Absonderung  bei  hochgradiger  Gefassverengerung 
Oder  Gefassverschluss  liegt  nichtin  dem  Sinken  des  Capillardruckes,  sondern  in  der, 
mit  der  kiinstliche  Anamie  der  Driise  verbundenen  Verlangsamung  des  Blutstromes, 
bei  welcher  sich  das  Secretions  Material,  und  namentlich  der  Sauerstoff  fiir  die 
Driisenzellen  allmalig  erschopft  so  dass  der  secretorische  Apparat  erstickt. ' ' 


SECRETION  PHYSIOLOGY.  309 

and  alveoli  are  compressed  and  the  liquid  in  them  ejected.  If 
that  liquid  is  thin  and  runs  readily,  as  in  most  albuminous 
glands,  for  example  the  parotid  and  submaxillary  of  the  rabbit, 
sheep  and  horse,  and  the  cat's  submaxillary,  or  in  mucous 
glands  after  long  stimulation,  the  latent  period  is  short,  and 
the  saliva  is  all  expelled  in  from  10—20  seconds.  Thereafter, 
although  contraction  persists,  no  more  secretion  escapes.  If, 
on  the  other  hand,  the  saliva  is  viscid,  as  in  the  first  stim- 
ulation of  a  previously  resting  mucous  gland  (submaxillary  and 
parotid  of  dog),  it  offers  a  great  resistance  in  passing  through 
the  fine  ducts  and  consequently  requires  a  greater  pressure  and 
a  longer  time  to  start  and  to  expel.  Consequently  the  latent 
period  is  long  and  the  secretion  persists  for  some  time.  This 
explains  the  anomalous  cases  represented  by  Experiment  III. 
In  cases  of  very  great  viscidity,  as  in  the  parotid  gland  of  the 
dog,  the  resistance  may  even  be  too  great  to  be  overcome  by  the 
compressing  strength  of  the  tissues.  In  this  gland  stimulation 
of  the  symyathetic  either  causes  no  secretion  at  all  or  very  lit- 
tle, unless  the  saliva  in  the  gland  be  previously  diluted  by  the 
action  of  the  dilator  nerve.  The  muscular  theory,  too,  readily 
explains  why  a  typical  sympathetic  secretion  can  ensue  in  the 
total  absence  of  blood  supply. 

b.  The  Decrease  in  the  Amount  of  Saliva  Obtainable  upon 
Several  Successive  Stimulations. 

If  one  sympathetic  stimulation  be  followed  by  several  others 
the  amount  of  saliva  obtainable  on  the  second,  or  followinsf 
stimulations,  is  much  less  than  the  first,  and  may  be  nothing  at 
all.*  If,  however,  the  gland  be  allowed  to  rest,  or  if  the  chorda 
be  stimulated,  the  nerve  again  produces  a  copious  secretion  upon 
sympathetic  stimulation.  This  is  shown  in  the  following  ex- 
cerpts from  experiments  on  the  dog's  and  cat's  submaxillary. 
Readings  in  mm.  Stimulation  in  each  case  for  thirty  seconds. 
It  is  also  clearly  seen  in   Experiment  VII,  p.  311. 

*This  phenomenon  has,  of  course,  been  often  described.  See  among  others 
Langley.39 

Annals  N.  Y.  Acad.  Sci.,  XI,  September  12,  189S — 21. 


310  MATHEWS. 

Cat.  Cat.  Dog. 

I.    '  II. 

Atnoimt.  Amount. 

1st  stimulation      .        .20 16 36 

Rest  .    .    .    .  25  seconds I  minute 2  minutes.      .    .    . 

2d  stimulation      .    .    .    .  o      .........  6 25 

Rest  ....    3  minutes 2  minutes    ....  I  minute    .... 

3d  stimulation  ....     H iO-5 ^^ 

j^ggl-  2  minutes      .    .    . 

4th  stimulation ^° 

j^est      I  minute    .... 

5th  stimulation ^^       .... 

Rest  .    .    .  • I  minute   .... 

6th  stimulation 2.5      .... 

Rest Chorda  stimulated    . 

7th  stimulation       25      .... 

Rest ^ 2  minutes      .    .    . 

8th  stimulation 6        .... 

Rest      I  min.  40  sec.  .    . 

9th  stimulation 4       •    •     '   • 

The  great  decrease  in  the  amount  of  saliva  obtainable  on  a 
second  stimulation,  closely  following  a  first,  even  though  a  min- 
ute's intreval  of  rest  elapse,  might  be  explained  on  Heidenhain's 
theory,  by  assuming  an  exhaustion  of  secretory  fibres,  nerve 
ends  or  gland  cells.  Such  an  assumption  is  highly  improbable. 
There  is,  I  believe,  no  other  example  of  a  nerve  end,  or  fibre, 
becoming  exhausted  by  a  weak  stimulus  of  a  minute's  duration. 
That  the  secretory  fibres  of  the  chorda,  their  nerve  ends  and 
the  gland  cells  are  not  exhausted  or  suffocated  is  shown  by  the 
fact  that  the  following  chorda  stimulation  is  little,  if  at  all,  al- 
tered. The  phenomena  are  clearly  explicable,  on  the  other 
hand,  if  the  Sympathetic  causes  secretion  by  compression  of  the 
ducts  and  alveoli.  By  the  first  stimulation  the  gland  is  largely 
emptied  of  its  saliva.  If  no  time  be  given  for  the  ducts  to  be 
refilled,  the  following  stimulation  finds  less  available  saliva,  or 
none  at  all.  The  nerve  appears,  in  fact,  to  have  become  inoper- 
ative until,  through  the  resting  of  the  gland,  or  the  action  of  the 
chorda,  the  ducts  be  again  filled.  The  exhausted  element  of 
the  gland  inferred  by  Heidenhain  is  the  fluid  in  the  ducts  and 
alveoli. 


SECRETION  PHYSIOLOGY.  311 

c.  The  Augmentation  of  Sympathetic  Saliva. 

That  the  small  amount  of  sympathetic  secretion,  in  the  cases 
just  cited,  is  due  to  the  presence  of  a  small  amount  of  fluid  in 
the  ducts  and  alveoli  is  indicated  by  the  abnormally  large  sym- 
pathetic secretion,  when  the  amount  of  liquid  sahva  in  the  gland 
is  rendered  abnormally  large  by  stimulation  of  the  chorda,  or  by 
the  action  of  pilocarpine,  nicotine  and  other  drugs. 

Langley^^  first  observed  the  augmentation  of  sympathetic 
saliva  by  an  immediately  preceeding  stimulation  of  the  dilator 
nerve  in  the  dog's  parotid  and  submaxillary  and  the  cat's  sub- 
maxillary. The  following  experiments  confirming  Langley  illus- 
trates this  augmentation. 

Experiment  VII. 

Dog  under  morphine  and  chloroform,  sympathetic  and  chorda 
cut.  Canula  in  Wharton's  duct.  Secretion  in  mm.  is  given 
above  the  line  for  every  lo  seconds,  250  mm.  =0.82  cc. 
Below  the  line  is  indicated  the  nerve  stimulated  ;  s,  is  the  sym- 
pathetic ;  c,  the  chorda.  If  no  letter  is  written,  it  indicates  that 
at  these  intervals  there  was  no  stimulation. 

10,  35.  3i>  2,  25,  4,  3,  2,  2,  8,  6,  4,  17,  2,  2,  I,  2,,  I,  3,  o 

c  sssss  ssssss 

3,  4,  i>^,  1^,  I,  2,  I,  4,  4,  i>  1=  I.  I.  !>  2.j[/^>  3,  I5  I,  o,  5,  I,  1,0 

sssss  ssss  sss  sss 

M!..°^.M^./^^.^^.^°A.3?A.^:.^^*:^^3>  I.  3.  3>  2,  2,  3,  2,  4,  ^^  

s                       cc                       ssss                            sss 
2,   I,   I,  2,   I,  45,  30,  3,  25,  2,    4,  2,  3,  2,  3,  I,   I,   I,  2, 


sss  c  ssss  ssss         c.  c.  c. 

%7;  3;   3;..2,    >^,  4,2.  2:,J^,    I,  ^.^!^.4>  0>,  O;. 

ssssss         sss  Chorda  i  minute    ssss 


4,  3,  2,  2,  I,  I,  3,  etc., 

sssss 


It  will  be  noticed,  in  this  experiment,  that  the  first  secretion  of 
the  sympathetic,  immediately  following  the  chorda  stimulation, 
is  abnormally  large,  but  that  the  augmentation  effect  rapidly 
passes  off.     The  augmented  saliva,  as  Langley  pointed  out,  is 


312  MATHEWS. 

more  watery  than  normal  and  has  a  shorter  latent  period.  It 
resembles  chorda  saliva.  A  similar  watery  and  copious  sym- 
pathetic saliva  occurs  after  the  injection  of  nicotine,^*  or  pilo- 
carpine,^" and  during  paralytic  secretion.^^ 

This  augmented  saliva  may  be  explained,  assuming  that  the 
nerve  acts  on  the  gland  cell,  as  follows  :  If  the  chorda  and  sym- 
pathetic act  as  the  same  gland  cells  (Heidenhain)  it  may  be  said 
that  stimulation  of  the  chorda  renders  the  cells  more  responsive 
to  a  sympathetic  stimulation  immediately  following.  If,  on  the 
other  hand,  the  chorda  and  sympathetic  innervate  different  gland 
cells  (Langley),  we  are  forced  to  the  assumption  that  nerve  im- 
pulses traverse  glands  outside  of  the  nerve  tracts.  "  When 
either  nerve  is  stimulated,"  Langley  says,  "there  is  an  irradia- 
tion of  impulses  of  less  intensily  to  the  cells  in  the  neighborhood 
of  those  directly  affected  ;  that  on  stimulation  of  the  chorda 
tympani  the  cells  connected  with  it  are  left  for  a  time  in  a  state 
of  weak  excitation,  so  that  irridiation  of  impulses  reaching  the 
gland  by  the  sympathetic  is  much  greater  than  normal,  and  these 
irradiating  impulses  being  weak  lead  to  a  more  fluid  secre- 
tion."^^ It  can  hardly  be  said,  I  think,  that  either  of  these  ex- 
planations is  satisfactory.  That  irritability  of  the  gland  cells 
probably  has  nothing  to  do  with  this  augmentation,  but  that  it 
is  the  simple  result  of  the  presence  of  an  abnormally  large 
amount  of  fluid  saliva  in  the  gland  is  shown  by  the  injection  of 
innocuous  fluid  into  Wharton's  duct.  By  this  means  we  pass- 
ively distend  the  ducts  and  aveoli,  without  the  intervention  of  cell 
activities.  Following  stimulation,  of  the  sympathetic  causes  an 
augmented  secretion.  I  have  tried  such  experiments  only  in  the 
case  of  the  dog's  submaxillary,  a  somewhat  unsatisfactory  gland, 
owing  to  the  viscidity  of  the  saliva.  The  experiment,  particu- 
larly if  tried  on  a  fresh  gland  full  of  viscous  saliva,  is  not  always 
successful.  The  cause  of  the  failures  has  not  been  investigated, 
but  I  suppose  they  are  due  to  the  unavoidable  driving  into  the 
gland  of  the  viscous  saliva  and  partly  to  the  use  of  too  great 
pressure  in  such  cases,  causing  an  over-distension  of  the  ducts 
and  a  consequent  injury  to  the  nerves.  The  positive  results  are, 
however,  sufficiently  conclusive. 


SECRETION  PHYSIOLOGY.  313 

Experiment  VIII. 

Small  dog  under  morphine  and  chloroform.  Left  submaxil- 
lary duct  and  nerves  prepared.  Nerves  cut.  The  chorda  is 
first  stimulated  intermittently  for  an  hour.  The  sympathetic  is 
stimulated  each  time  for  30  seconds.  Secondary  coil  70.  Se- 
cretion in  mm.  as  before. 

Time.  Nerve  Secretion. 

h.  m.  s. 
3  30  Sympathetic  10 

3  32  "  4 

Inject  '3CC.  0.6%  NaCl  solution  into  Wharton's  duct. 
3  34  Sympathetic  15 

3  36 


o 

o 

II 


3  41 

4  10 

4  II 

4   12   30 

Inject  y^  cc.  0.5%  NaCl  into  duct. 

4  14  Sympathetic 

4   15 


Experiment  IX. 

Conditions  of  experiment  as  in  8.     Dog  larger.      Sympathetic 
30  seconds  stimulation,  unless  otherwise  indicated. 

Secretion  in  mm. 


40 

15 
20 
10 
20 
18 

40 

7 
o 

n 

2 

o 

11 


Time. 

Nerve. 

1.  m.  s 

5  20 

Sympathetic 

5  22 

" 

5  24 

-5  25 

5  26 

" 

5  27 

-5  27  40 

5  28 

-5  28  40            " 

Inject 

.4  cc.  0.6%  NaCl  into  duct 

5  30 

Sympathetic 

5  31 

" 

5  32 

" 

Inject 

.3  cc.  0.6%  NaCl. 

5  34 

Sympathetic 

5  35 

(C 

5  36 

" 

Inject 

3  cc.  0.6%  NaCl. 

538 

Sympathetic 

314  MATHEWS. 

The  results  of  these  experiments,  in  conjunction  with  those 
following,  are  most  readily  explicable,  I  believe,  on  the  muscu- 
lar theory.  The  augmented  saliva,  in  whatever  manner  pro- 
duced, gives  fairly  conclusive  evidence  that  the  nerve  causes 
secretion  by  compression  of  the  ducts  and  alveoli.  If  these  are 
filled  with  an  unusually  large  amount  of  fluid  saliva  an  unusu- 
ally large  secretion,  characterized  by  its  short  latent  period  and 
watery  character,  is  secreted.  If  there  be  little  saHva  present, 
or  if  it  be  very  viscous,  we  obtain  a  small  secretion  of  long  latent 
period  and  lasting  for  some  time. 

{d)  Paralysis  of  the  Sympathetic  by  Emptying  the  Ducts 

AND    ITS    ReSTORAL   TO    PoWER    BY    INJECTION    OF 

Fluid  into  the  Ducts. 

Further  strong  evidence  of  the  muscular  action  of  the  sympa- 
thetic may  be  obtained  by  preventing  the  passage  of  fluid  into  the 
gland  and  stimulating  the  nerve  until  all  available  saliva  in  the 
ducts  has  presumably  been  expelled.  The  nerve  then  appears 
to  have  lost  its  action,  but  it  may  be  shown  to  be  still  active  by 
the  injection  of  fluid  into  the  ducts.  The  passage  of  fluid  into 
the  gland  may  be  prevented  either  by  the  use  of  quinine  or  by 
compression  of  the  gland  artery. 

Heidenhain  *  showed  that  if  quinine  sulphate  be  injected  into 
Wharton's  duct  the  secretory  action  of  the  chorda  is  ultimately 
paralyzed,  but  the  gland  becomes  oedematous.  This  indicates 
that,  although  liquid  is  present  in  the  lymph  spaces,  it  is  pre- 
vented in  some  way  from  passing  through  the  cell.  If,  after 
paralysis  of  the  chorda,  the  sympathetic  be  stimulated,  a  copious 
secretion  is  obtained.  After  a  few  stimulations,  however,  the 
nerve  appears  to  be  paralyzed.  If  that  paralysis  is  only  apparent, 
due  to  the  emptiness  of  the  gland's  ducts,  we  should  be  able  to 
obtain  a  secretion  on  sympathetic  stimulation,  by  the  injection 
Into  the  duct  of  more  quinine  sulphate.  The  following  experi- 
ment proves  this  to  be  the  case. 

*  Heidenhain,  Studien  aus  Breslau,  IV,  1868. 


SECRETION  PHYSIOLOGY.  315 


Experiment  X. 

Large  dog.  Operation  as  in  other  experiments.  Secretion 
in  mm.  250  mm.  =  0.82  cc,  s=sympathetic  ;  c=chorda. 

Time.  Nerve.  Coil  in  cm.  Secretion  in  mm. 

h.  m.  s. 

12  24 s  . 15 72 

12  25 s 15 12 

Chorda  stimulated  for  several  minutes,  then  .5  cc.  of  saturated  solution  of  qui- 
nine sulphate  injected  slowly  into  Wharton's  duct. 

12  37 c 13 o 

12   38 C II o 

12  39 s II 50 

12  40  ......  s II 27 

12  44 s •   ...  15 12 

12  45 s 15 9 

12  47 c II o 

12  48 c 7 o 

12  50 s 14 15 

12  54 c  .    . II o 

12  55 s 14 7 

12  57 s 13       10 

12  59 s 13  ........    3 

Inject  mixture  equal  parts  0.6%  NaCl  and  sat.  quinine  sulphate. 

I  03 s  . 13 24 

I  OS s 13 4 

I  09 s 12 o 

I  10 s 9 I 

III S ID O 

Neither  nerve  produces  a  secretion,  though  stimulated  from  time  to  time. 

4  00 c 8 o 

4  01 s 8 o 

Inject  0.5  %  NaCl  into  duct. 

4  02      s 6.5 32 

4  03 s 6 14 

4  06 s 6 3 

4  09  Inject  HCl  0.5%  into  duct. 

4  10 s 6      9 

Chorda  ineffective  at  any  strength. 

In  the  foregoing  experiment  the  chorda  became  completely 
ineffective  at  12:30.  The  gland,  however,  was  abnormally  full 
of  quinine  fluid,  and  the  first  sympathetic  stimulation  after  the 


316  MATHEWS. 

injection  consequently  gave  a  greatly  augmented  secretion  at 
12:39.  Thereafter  each  stimulation  yielded  less  and  less,  and 
finally  at  12:59  o^^X  3  "^"^-  '^^'^''^  secreted.  The  ducts  may  be 
assumed  to  be  practically  empty.  Quinine  solution  was  now 
again  injected,  and  the  next  sympathetic  stimulation  yielded 
again  a  greatly  augmented  secretion.  Finally  at  i:i  i  the  sym- 
pathetic failed  to  yield  any  secretion,  and  from  then  until 
4  p.  M.  was  totally  ineffective.  It  would  be  said,  at  first  sight, 
that  the  nerve  was  paralyzed.  Such,  however,  was  not  the 
case,  its  seeming  paralysis  being  due  to  the  Emptiness  of  the 
gland.  This  was  shown  by  the  injection  of  .5  %  NaCl  solution 
into  the  duct.  The  following  stimulation  of  the  sympathetic  at 
4:02  yielded  a  very  large  secretion. 

This  experiment  in  two  ways  furnishes  very  strong  evidence 
of  the  muscular  nature  of  the  sympathetic  secretion.  The  fact 
that  sympathetic  secretion  may  be  obtained  long  after  paralysis 
of  the  chorda  is  very  suggestive.  Heidenhain*  maintains  that 
the  chorda  secretion  is  paralyzed  by  the  action  of  the  drug  on 
the  gland  cells.  If  this  be  true,  and  I  see  no  reason  to  doubt 
it,  it  furnishes  very  strong  evidence  that  the  sympathetic  pro- 
duces its  secretion  in  sonic  other  manner  than  action  on  the  gland 
cell,  for  the  sympathetic  secretion  is  not  materially  affected  long 
after  the  gland  cells  have  been  completely  paralyzed.  The  fact 
that  the  nerve's  effect  soon  passes  away,  but  may  be  restored 
by  the  simple  injection  of  more  quinine  solution  or  other  fluid 
into  the  duct,  I  believe  to  be  susceptible  of  but  one  explanation, 
z.  c.,  that  the  nerve  causes  this  secretion  by  compression  of  the 
ducts  and  alveoli. 

A  similar  phenomenon  is  witnessed  if  the  gland  artery  be 
compressed  and  fluid  thus  cut  off  from  the  gland.  A  few  stimu- 
lations of  the  sympathetic  sufiflce  to  render  the  nerve  inoperative, 
but  by  injection  of  fluid  into  the  duct  the  nerve  is  shown  to  be 
still  active. 

'"  Heidenhain,  Studien  aus  Breslau,  IV,  i868,  p.  85,  "so  wird  die  Erregbarkeit 
der  absondernden  Elemente  bald  herabgesetzt  und  nach  kurzer  Zeit  ganz  vernichtet. ' ' 


SECRETION  PHYSIOLOGY.  317 


Experiment  Va  (Continued;  see  p.  305). 

Time.  Nerve.  Secretion  in  mm. 

h.  m.  s. 

3  25 Artery  clamped  close  by  the  hilus. 

3  30 Chorda .    .     O 

3  35 SjTiipathetic  23 

3  37 Sympathetic o 

3  40 Sympathetic o 

0.2  cc,  .5  %  NaCl  solution  injected  into  duct. 
3  41 Sympathetic •   •  1? 

3  42 Artery  undamped 

4  07  30 Artery  clamped 

4  12 Chorda o 

4  13 Sympathetic 25 

4  15-4  17    ...    .  Chorda o 

4  17  30-4  18  15     .  Sympathetic 14 

4  20 Sympathetic  ......    o 

4  23 •  -3  cc.,  .5  %  NaCl  injected  into  duct 

4  24 S}Tnpathetic  ....  13 

4  25 Sympathetic o 

4  26-4  27      ....  Sympathetic o 

4  28 2  cc,  .5  %  NaCl  injected 

4  29 Sympathetic 8 

In  this  experiment  the  sympathetic  appeared  paralyzed  at 
3:40,  4:20  and  4:26,  but  the  injection  of  normal  salt  solution 
into  the  duct  was  followed  by  a  secretion  little  less  than  normal, 
on  the  next  stimulation.  In  one  case  twenty  minutes  after  the 
artery  had  been  clamped,  the  sympathetic  was  thus  shown  still 
to  be  active.  Heidenhain  attributes  the  loss  of  the  chorda's 
power  to  the  suffocation  and  consequent  paralysis  of  the  gland 
cell.  (See  footnote,  p.  308.)  As  already  pointed  out  (p.  316)  this 
would,  if  true,  show  that  the  sympathetic  produces  its  secretion 
in  some  other  way  than  by  action  on  the  cell.  The  fact  that 
the  nerve's  power  may  be  restored  by  the  injection  of  innocuous 
fluid  into  the  ducts  is  readily  explicable  on  the  muscular  theory 
of  secretion,  but,  with  difficulty,  on  the  cellular  theory. 

I  found  that  a  similar  phenomenon  may,  at  times,  be  seen  in 
the  cat's  submaxillary,  which  has  been  paralyzed  by  just  suffi- 
cient atropin  to  prevent  chorda  secretion.  As  was  first  pointed 
out  by  Langley,  atropin  paralyzes  the  sympathetic  in  the  cat, 
but  more  atropin  is  required  than  to  paralyze  the  chorda.      The 


THfOLOGlCAl    Sew,NARY 


318 


MATHEWS. 


sympathetic  may  appear  paralyzed,  wholly  or  in  part,  before  it 
actually  is.  In  this  condition  gently  forcing  the  secreted  saliva 
back  into  the  gland  restores  the  nerve's  power. 

Experiment  XII. 

Cat  etherized.  Canula  in  duct  of  left  submaxillary.  Both 
chorda  and  cervical  sympathetic  cut.  Both  nerves  active.  In- 
ject .1^  solution  of  atropin  carefully  into  femoral  vein  until 
chorda  just  paralyzed.  Sympathetic  stimulated  30  seconds 
each  time. 


Time. 

Nerve. 

Secretion  in  cc 

h.  m. 

s. 

3  50 

Chorda 

0. 

3  51 

Sympathetic 

0 

I 

3  52 

" 

0 

I 

3  53 

(( 

0 

I 

3  54 

(f 

0 

05 

3  55 

" 

0 

05 

3  56 

C( 

0 

03 

Blew  the  secretion  gently  back 

into 

gland. 

3  57 

Sympathetic 

0.13 

4  00 

li 

0 

15 

4  06 

Inject  .1  cc.  atropin  into  femoral 

vein 

4  07 

Sympathetic 

0 

10 

4  08 

" 

0 

10 

4  09 

a 

0 

10 

4  10. 

Sympathetic 

Inject  .2  cc.  atropin 

•    • 

•    •    • 

•    • 

.10 

4  13 

Sympathetic  . 

.    .    . 

.07 

4  14 

££ 

.01 

4  15 

,i 

.0^ 

Blew  saliva  into  gland. 

4  16 

Sympathetic . 

.    . 

.    .    . 

.25 

4  17 

a 

.05 

4  18 

(.i 

.04 

4  19 

iC 

.02 

Blew  .  I  cc.  saliva  back  into 

gland. 

4  20 

Sympathetic . 

.    . 

.   .    • 

.   . 

.12 

4  21 

" 

.04 

4  22 

<< 

•03 

Blew  .  I  cc.  saliva  back  into  gland. 


SECRETION  PHYSIOLOGY.  319 

4  23 Sympathetic 14 

4  24 " 02 

4  25 " .04 

4  26 " 02 

Blew  .  I  cc.  saliva  back  into  gland. 

427 Sympathetic 13 

4  28 "       01 

4  29 " 06 

4  30 " 02 

4  31 " 03 

Blew  .  I  cc.  saliva  back  into  gland. 

4  32  ,.,...    .  Sjmpathetic 10 

4  33 " 02 

4  34 " 05 

4  35 " -04 


26 


Blew  back  .1  cc.  saliva. 

437 .  Sympathetic 12 

4  38 " 04 

4  39 " 01 

4  40  ,    . " 04 

4  41 " 03 

Blew  back  .1  cc.  saliva. 

4  42 Sympathetic 09 

4  43 " 03 

4  44 " 04 

4  45 " 02 

Blew  back  .  i  cc.  saliva. 

4  46 Sympathetic 10 

4  47 " 05 

4  48 " 03 

4  49 " 04 

4  50 "       02 

Blew  back  .  i  cc.  saliva. 

4  51 Sympathetic 11 

4  52 " 02 

4  53 " 04 

4  54      ..." 025 

Blew  back  .1  cc. 

4  55 S 075 

4  56 S 025 

4  57 S 04  &c. 

The  most  probable  explanation  of  the  apparent  failure,  partial 
or  total  of  the  sympathetic,  in  all  the  immediately  preceding 
experiments,  appears  to  me  to  be  this  :  That  by  the  injection  of 


320  MATHEWS. 

quinine,  or  atropin,  or  compression  of  the  gland's  artery,  liquid 
is  prevented  from  entering  the  gland.  A  few  stimulations  of 
the  sympathetic  suffice  to  expell  all,  or  most,  of  the  available 
saliva  in  the  gland,  and  the  nerve  thereafter  appears  paralyzed. 
If,  now,  the  ducts  and  alveoli  be  passively  redistended  by  the 
injection  of  liquid  into  the  duct  the  nerve  again  causes  a 
compression  of  the  duct,  and  the  fluid  is  again  expelled  and  gives 
a  secretion.  This  renewed  secretion  cannot,  however,  be  re- 
ferred to  the  action  of  the  gland  cell,  because  the  latter  has  been 
in  one  case  paralyzed  by  the  action  of  quinine,  and  in  the  other 
case  by  suffocation.  Nor  could  it  be  referred  to  the  action  of 
the  cell,  even  were  the  latter  not  paralyzed,  for  the  mere  hypo- 
thetical taking-up  of  fluid  into  the  cell  from  the  duct,  and  its 
discharge  again  into  the  latter,  would  in  no  way  alter  the  bulk 
of  fluid  in  the  ducts  plus  the  bulk  of  the  cell.  There  would, 
hence,  be  no  pressure  to  drive  the  secretion  from  the  gland. 

e.  The  Character  of  Sympathetic  Saliva. 

Evidence  that  the  sympathetic  nerve  innervates  the  gland  cell 
has  been  derived  from  the  character  of  the  sympathetic  saliva. 
This,  as  is  well  known,  is  richer  in  organic  matters  than  the 
saliva  secreted  under  the  influence  of  the  gland's  dilator  nerve. 
This  greater  richness  Heidenhain  attributes  to  the  predominance 
in  this  nerve  of  so-called  "  trophic  "  fibres,  the  function  of  which 
is  to  render  the  stored-up  metabolic  products  of  the  cell  (hylo- 
gens)  more  soluble,  and  the  juice  consequently  more  concen- 
trated. This  assumption  involves  such  consequences  that  by 
common  consent  it  has  been  considered  the  most  unsatisfactory 
part  of  the  Heidenhain  theory.  It  is,  however,  practically  the 
only  probable  explanation,  with  one  exception,  which  has  been 
offered.  The  exception  is  the  view  suggested  by  Schiff,  dis- 
cussed below. 

If  the  sympathetic  simply  drives  out  the  saliva  already  present 
in  the  gland  the  sympathetic  saliva  must  be  of  the  character  of 
that  present  in  the  ducts  and  alveoli  at  the  moment  of  stimulation. 
There  is  evidence  that  this  is  the  case.  That  the  saliva  in  the 
ducts  of  the   dog's  parotid  is   very  viscid  has  been  shown  by 


SECRETION  PHYSIOLOGY.  321 

Langley.''^  Sections  show  the  ducts  plugged  with  a  viscous 
looking  mass,  and  Langley  suggests  that  the  saliva  is  here  too 
thick  to  be  expelled.  In  one  experiment  Langley  found  a  dog's 
parotid  which  secreted  under  the  influence  of  the  sympathetic 
1.3   cc.      Concerning  this  saliva  Langley  says  •}'^ 

"  The  saliva  was  of  the  most  remarkable  nature  ;  it  formed  a 
thick  jelly-like  mass  ;  if  allowed  to  collect  at  all  in  the  canula 
it  could  be  drawn  out  as  a  continuous  clot.  During  the  experi- 
ment the  duct  was  frequently  emptied  by  pressure  to  prevent 
its  being  stopped  up."  The  saliva  contained  7.8  %  of  organic 
solids.  We  can,  moreover,  artificially  alter  the  fluidity  of  the 
saliva  in  the  ducts,  rendering  it  more  dilute,  by  the  action  of  the 
chorda  tympani  or  pilocarpine.  In  such  cases,  as  we  have  seen 
in  speaking  of  the  augmented  secretion,  sympathetic  saliva  is 
almost  as  thin  as  chorda  saliva.  By  long  stimulation  of  the 
chorda,  moreover,  we  may  exhaust  the  soluble  constituents  of 
the  gland.  In  such  cases  it  may  be  presumed  that  the  gland 
saliva  is  thinner  than  normal.  It  is  known  that  under  such  cir- 
cumstances the  sympathetic  saliva  may  fall  within  the  limits  of 
density  of  chorda  saliva.*  A  similar  change  occurs  in  paralytic 
secretions  following  division  of  the  chorda.  The  gland  then 
secretes  a  very  thin  saliva,  and  sections  show  the  cells  practic- 
ally exhausted  of  their  mucous.  The  sympathetic  in  these 
causes  a  very  abundant  and  very  watery  secretion. 

We  may  obtain  still  further  evidence  of  the  character  of  the 
saliva  normally  present  in  the  ducts  of  the  resting  gland  by  a 
sudden,  strong  stimulation  of  the  chorda  tympani.  The  rapid 
inflow  of  fluid  from  the  capillaries  about  the  alveoli,  taking  place 
under  the  influence  of  that  nerve,  drives  out  the  saliva  in  the 
ducts  before  it  has  time  to  become  diluted.  If  we  examine  this 
saliva  first  appearing  on  chorda  stimulation  we  find  it  in  all  re- 
spects typical  sympathetic  saliva.  From  this  Schiff  concludedf 
that  sympathetic  saliva  was  nothing  more  than  the  saliva  nor- 
mally present  in  the  ducts,  formed  during  glandular  rest. 

*  Heidenhain,  Studien  aus  Breslau,  IV,  1868.  After  long  sympathetic  stimula- 
tions the  saliva  becomes  "  diinnflussig,  hell,  und  dadurch  dem  chorda  Speichel 
ganz  und  gar  ahnlich." 

t  Schiff.     LeQons  sur  la  Digestion.       Tome  I.,  p.  296,  1867  ;  also  p.   304. 


322  MATHEWS. 

Schiff  found  that  if  the  sympathetic  nerve  of  the  horse  be 
stimulated  the  parotid  secreted  quickly  8— lo  volumes  of  white 
saliva,  and  then,  as  in  the  cat's  submaxillary,  secretion  ceased. 
If  the  horse  be  fed  there  ensued  a  copious,  clear  secretion  of 
watery  cerebral  saliva.  The  gland  was  now,  presumably,  full 
of  such  saliva.  If  it  be  allowed  to  rest  for  twenty  min- 
utes without  secretion  on  again  feeding  the  horse  the  first 
saliva  (8-io  volumes)  zvas  typical,  thick,  ivhitc  syinpatlietic 
saliva.  This  was  followed  by  the  clear  cerebral  saliva.  Schiff 
repeated  this  many  times,  thus  showing  that  in  the  interval  of  rest 
the  gland,  uninfluenced  by  the  sympathetic,  converts  the  clear 
cerebral  saliva  into  typical  so-called  sympathetic  saliva.  A  sim- 
ilar phenomenon  has  been  described,  with  a  somewhat  different 
interpretation  for  the  dog's  submaxillary,  by  Heidenhain.*  I 
have  repeated  Schiff's  experiment  on  the  dog's  submaxillary, 
fully  confirming  him.  This  is  shown  in  the  following  exper- 
iment. 

Experiment  XIII. 

Large  dog,  morphine  and  ether.  At  10:30  a.  m.  canula  in 
right  Wharton's  duct.  Sympathetic  and  chorda-lingual  cut. 
On  the  first  stimulation  of  the  chorda  the  first  saliva  was  viscid, 
whitish  and  filled  with  corpuscles.  The  chorda  Avas  stimu- 
lated until  2  cc.  of  saliva  were  secreted.  This  saliva  was  thin, 
clear,  typical  chorda  saliva.  Gland  rested  without  secretion 
until  11:30.  Stimulated  chorda.  The  first  saliva  zvas  thick, 
viscid,  white  saliva.  The  gland  then  secreted  i  cc,  clear 
chorda  saliva.  Rested  until  2:30  P.M.  Stimulated  the  chorda. 
A  very  large  amount  of  typical,  sympathetic  saliva  appeared  first, 
followed  by  2  cc.  of  watery  chorda  sahva.  Gland  rested  until 
4  P.  M.  Stimulated  chorda.  The  first  saliva  was  viscid  and 
contained  many  salivary  corpuscles.  Secreted  afterward  i  cc. 
clear  saliva.  Rested  until  5  p.  m.  Stimulated  the  chorda. 
The  first  saliva  zvas  again  viscid,  zvhitish  saliva,  filled  zvitli  sali- 
vary corpuscles  and  lumps. 

*  Heidenhain.  Studien  aus  Breslau,  IV,  1868,  p.  52.  "Die  erste  Speichel  por- 
tion war  sehr  dick,  fast  gallertartig,  reich  an  Schleimballen  wie  sie  sonst  im  Sympa- 
thicus  Speichel  vorkommen,  und  ebenso  an  Speichelkorperchen  die  haufenweise 
bei  einander  lagen." 


SECRETION  PHYSIOLOGY.  323 

This  experiment  proves  that  after  each  stimulation  of  the 
chorda,  the  thin,  chorda  saHva  filHng  the  gland  ducts  is  quickly 
converted,  even  in  the  absence  of  sympathetic  influence,  into 
typical  viscid,  sympathetic  saliva.*  It  shows,  also,  that  the  ducts 
of  the  normal,  resting  mucous  gland  are  filled  with  saliva,  sup- 
posed to  be  characteristic  of  the  sympathetic's  action.  This 
observation  seems  to  me  to  render  Heidenhain's  assumption  of 
special  "trophic"  nerve  fibres  to  account  for  the  character  of 
such  saliva,  superfluous  ;  and,  also,  to  give  additional  evidence 
that  sympathetic  saliva  is  nothing  more  than  this  "  saliva  of 
rest,"  expelled  by  compression  of  ducts  and  alveoli.  The  cor- 
rectness of  the  latter  view  is,  in  my  opinion,  strongly  confirmed 
by  the  great  variation  in  character  of  sympathetic  saliva,  with  a 
variation  of  character  of  the  saliva  within  the  gland. 

I  wish  to  point  out,  also,  that  the  influence  of  sympathetic 
stimulation  upon  the  composition  of  the  saliva  secreted  during 
coincident  stimulation  of  the  dilator  nerve,  upon  which  special 
stress  has  been  laid  by  Heidenhain,  is  also  readily  understood  on 
this  hypothesis  of  the  nature  of  sympathetic  action.  Langley's 
discovery'^^  that  the  sympathetic  produces  a  secretion  from  the 
dog's  parotid  unless  the  saliva  be  too  thick  for  expulsion  make 
Heidenhain's  results  clear." 

Heidenhain  found,  in  harmony  with  all  other  observers,  that 
stimulation  of  the  sympathetic  usually  causes  no  secretion  from 
the  dog's  parotid.  He  concluded  from  this  that  the  nerve 
carried  no,  or  few,  secretory  fibres. f  He  discovered,  however, 
that  if  Jacobson's  nerve  be  irritated  so  as  to  cause  a  secretion, 
and  during  this  irritation  the  sympathetic  be  stimulated,  the 
saliva  secreted  during  simultaneous  irritation  of  both  nerves  was 
far  richer  in  organic  solids  than  that  secreted  under  the  influ- 
ence of  Jacobson's  nerve  alone.;};      Denying  that  the  sympathetic 

■    *  This  is  a  pretty  conclusive  reply  to  the  statement  of  Heidenhain  that  the  simple 
contact  of  the  water  with  thehylogens  is  not  sufficient  to  dissolve  them 
We  have  here  a  demonstration  that  it  is  sufficient  in  the  total  absence  of  nerve  in- 
fluence. 

t  Heidenhain.  Hermann's  Handbuch  d.  Phys.  V,  p.  55.  "  Der  Sympathicus 
des  Hundes  enthalt  fiir  die  Parotis  nur  trophische,  fiir  die  submaxillaris  daneben 
wenige  secretorische  Fasern." 

j  Heidenhain,  Hermann's  Handbuch  d.  Phys.  V,  p.  55. 


824  MATHEWS. 

exerted  a  secretory  effect  upon  the  gland,  he  considered  the 
secretion  to  be  due  to  Jacobson's  nerve  alone.  He  concluded, 
therefore,  that  stimulation  of  the  sympathetic  enormously  in- 
creased the  content  of  organic  solids  in  the  cerebral  saliva.  The 
sympathetic  must  hence  act  on  the  gland  cells  so  as  to  render 
their  contents  far  more  soluble.  From  Langley's  results,  how- 
ever, we  can  safely  conclude  that  the  saliva,  secreted  when  both 
nerves  are  stimulated,  is  not  pure  cerebral  saliva,  but  largely,  if 
not  wholly,  augmented  sympathetic  saliva.  Like  all  sympa- 
thetic saliva,  it  is  more  concentrated  than  the  saliva  secreted 
under  the  influence  of  the  dilator  nerve,  because  it  is  expelled 
without  dilution. 

f.  Other  Evidence  of   the  Muscular  Nature  of  the 
Mechanism  of  Sympathetic  Secretion. 

Very  clear  evidence,  also,  has  been  brought  forward  by  Eck- 
hard,^^  von  Wittich"''  and  Heidenhain^^  himself  that  the  sympa- 
thetic causes  at  least  the  major  part  of  its  secretion,  by  a  com- 
pression of  the  ducts  and  alveoli.  The  parotid  gland  of  the 
sheep  is  an  albuminous  gland,  capable  of  secreting  against  a 
pressure  of  400-500  m.  m.  of  water  (Eckhard).  If  while  secret- 
ing against  a  somewhat  lower  pressure  (200—300  mm.)  the 
cervical  sympathetic  be  stimulated,  the  water  rises  suddenly  in 
the  manometer  for  some  distance  (30-100  mm.).  On  ceasing 
stimulation  the  secretion  riislies  hack  at  once  into  the  gland  nearly, 
tho?igh  never  quite,  to  its  former  level.  The  higher  the  pressure 
the  more  sudden  the  flow  backward.  The  quick  rise  at  the 
beginning  of  stimulation  and  the  abrupt  back  flow  of  the  secretion 
at  the  end  plainly  suggest  that  the  nerve  caused  compression 
of  the  ducts  and  alveoli,  and  thus  pressed  out  the  secretion. 
On  ceasing  stimulation  these  structures  dilated,  and  the  secre- 
tion, being  under  pressure,  rushed  back  into  the  gland.  I  see 
no  other  explanation  for  the  back  flow,  as  it  takes  place  too 
suddenly  and  at  too  low  a  pressure  (200  mm.  water)  to  be  due 
to  back  filtration. 

Heidenhain's  observation  is   less  striking,  but  it  is  similar  to 


SECRETION  PHYSIOLOGY.  325 

the  above.  (Breslau  Studien,  p.  69,  IV.)  In  taking  the  secre- 
tory pressure  of  the  dog's  submaxillary  he  stimulated  the 
chorda  until  the  pressure  in  the  ducts  was  271  mm.  Hg.  On 
ceasing  stimulation  the  manometer  gradually  fell.  On  stinnila- 
tiiig  the  syTiipatJictic  the  sinking  became  unicJi  slcnver,  and  the  ma- 
nometer remained  stationary  at  160  mm.  On  breaking  the 
stimulation  the  manometer  sank  gradually  to  100.  On  stimu- 
lating the  sympathetic  it  rose  to  107,  and  on  chorda  stimulation 
to  271.  It  gradually  fell  during  following  sympathetic  stimula- 
tion, but  on  bi^eaking  the  stinmlation  it  fell  with  striking  rapidity 
(Auftalig  beschleunigtes  Sinken).  Heidenhain  thus  records  for 
the  dog's  submaxillary  the  same  sudden  back  flow  on  breaking 
the  stimulation  of  the  sympathetic  as  Eckhard  and  von  Wittich 
describe  in  the  sheep. 

Paradoxical  though  it  may  seem,  the  experiments  just  quoted 
of  von  Wittich  and  Eckhard  have  been  cited  by  Heidenhain  as 
conclusive  evidence  that  the  sympathetic  does  not  simply  drive 
out  the  secretion  already  in  the  gland.  And  it  is  this  con- 
viction which  led  Heidenhain,  in  the  discussion  of  all  experi- 
ments involving  the  sympathetic,  to  ignore  the  possibility  of  its 
having  such  an  action.  Heidenhain  believed  von  Wittich  was 
right  in  contending  that  the  failure  of  the  manometer  to  return 
to  its  former  level  on  breaking  stimulation  proved  that  the 
amount  of  saliva  in  the  gland  had  been  increased.  It  will  be 
instructive  to  consider  von  Wittich's  explanation  of  the  phe- 
nomena of  this  secretion,  von  Wittich''''  suggests  that  the  back 
flow  of  the  saliva  is  due  to  the  saliva  being  pushed  back  into  the 
cells.  Let  us  examine  this  more  closely.  von  Wittich  and 
Heidenhain  assumed  that  the  cells,  on  stimulation,  discharge 
their  stored  products  into  the  lumen.  Such  a  process,  it  need 
hardly  be  said,  would  lead  to  no  secretion  from  the  ducts,  as 
the  bulk  of  the  cell  would  diminish  to  just  the  extent  that  the 
bulk  of  fluid  in  the  ducts  increases.  Hence  the  bulk  of  cell 
plus  liquid  would  remain  unaltered.  We  must,  therefore,  make 
either  one  of  two  farther  assumptions  :  First,  that  the  alveoli  are 
greatly  distended  owing  to  the  turgor  of  the  cells.  Stimulation 
of  the  nerve  might  conceivably  diminish  the  resisting  power  of 

Annals  N.  Y.  Acad.  Sci.,  XI,  September  13,  1898 — 22. 


326  MATHEWS. 

the  inner  end  of  the  cell,  and  the  secretion  be  expelled  from  the 
cell  by  intra-cellular  tension,  and  from  the  ducts  by  the  elastic 
tension  of  the  distended  alveolar  wall.  Or,  second,  it  must  be 
assumed  that,  as  the  fluid  flows  from  the  cell,  new  fluid  enters 
the  cell  from  the  rear,  so  that  the  cell  does  not  diminish  in  bulk 
to  an  extent  aqual  to  the  bulk  of  secretion  it  has  lost.  Either 
of  these  assumptions  lands  us  at  once  in  difficulties.  If  the  first 
be  true  we  cannot  understand  why  the  sympathetic  secretion 
should  be  abnormally  large,  just  in  those  cases,  such  as  par- 
alytic secretions,  or  after  long-continued  chorda  secretion,  in 
which  the  alveoli  are  not  distended  and  are  not  presumably 
under  pressure.  The  second  assumption,  besides  being  wholly 
imaginary,  has  to  explain  whence  comes  the  fluid  flowing  into 
the  cell,  and  why  it  should  flow  in  during  sympathetic  stimu- 
lation at  a  time  when  there  is  a  pronounced  vaso-constriction. 
With  this  difficulty  of  understanding  how  the  nerve  could  cause 
a  secretion  by  action  on  the  cell,  let  us  see  how  the  sudden  back 
flow  could  be  understood.  According  to  von  Wittich  and 
Heidenhain  the  diameter  of  the  alveoli  has  remained  constant. 
The  secretion,  manifestly,  cannot  upon  this  assumption  return 
into  the  gland,  unless  there  be  a  diminution  in  the  combined 
bulk  of  the  secretion  in  the  ducts  and  the  cells.  There  will  be 
no  such  alteration  in  bulk,  however,  by  the  secretion  passing  into 
the  cell  as  von  Wittich  assumes,  for  the  cell  will  grow  to  just 
the  amount  that  the  secretion  in  the  lumen  diminishes.  The 
only  way  a  diminution  in  bulk  could  be  brought  about  is  by  a 
back  filtration.  The  fall  is,  however,  much  too  sudden  for  this, 
and  takes  place  at  a  pressure  much  less  than  the  gland  can  sus- 
tain without  becoming  oedematous.  It  is  also  impossible  to  see 
why  on  ceasing  stimulation  the  permeability  of  the  gland  to  back 
filtration  should  suddenly  increase.  Easy  though  it  seems  at 
first  sight,  therefore,  to  ascribe  such  a  back  flow  to  a  reabsorp- 
tion  under  pressure  of  saliva  by  the  cell,  closer  inquiry  shows 
that  it  is  impossible  to  account  for  this  back  flow  except  on  the 
assumption  either  of  a  back  filtration  or  that  there  has  been  an 
alteration  in  the  diameter  of  the  alveoli.  I  maintain  with  Eck- 
hard  that  a  back  filtration  is   highly  improbable,  and  there  re- 


SECRETION  PHYSIOLOGl.  327 

mains  only  the  alternative  of  an  increase  in  the  diameter  of  the 
alveoli,  probably  following  an  active  compression. 

But  if  the  saliva  is  simply  pressed  out,  why  is  it  that  it  does 
not  return  to  its  former  level  on  ceasing  stimulation  ?  This  was 
supposed  by  von  Wittich  to  prove  that  the  nerve  increased  the 
amount  of  saliva  in  the  gland.  I  fully  agree  with  von  Wittich 
in  this  contention,  but  I  disagree  with  him  entirely  in 
referring-  the  increase  to  the  action  of  the  nerve  on  the  cell 
This  increase  maybe  readily  understood  on  the  muscular  theory, 
without  any  assumption  of  nerve  activity  on  the  gland  cell,  as 
follows  :  On  breaking  sympathetic  stimulation  of  considerable 
duration  a  temporary  vaso-dilation  occurs  and  the  ducts  and 
alveoli  relax.  It  takes  an  appreciable  time  for  the  saliva  to  pass 
back  into  the  fine  tubules,  and  during  this  time  the  cells  are  ab- 
sorbing water  from  the  lymph  and  capillaries.  Hence  their 
bulk  and  the  amount  of  saliva  is  increased  and  the  saliva  is 
never  able  to  return  to  its  former  level.  The  proof  of  this  is 
sufficiently  clear.  That  vaso-dilation  does  occur  temporarily  on 
ceasing  stimulation  of  constrictor  nerves  has  often  been  re- 
marked. I  have  myself  often  seen  it  in"  the  rabbit's  ear  and  in 
the  cat's  submaxillary.  In  the  dog's  submaxillary  I  have  often 
seen,  also,  that  coincident  with  this  vaso-dilation  a  slight  secre- 
tion may  actually  ensue  (See  Expt.  VII,  p.  3 1 1).  It  is,  also,  well 
established  that  the  cells  do  imbibe  fluid  and  food  during  or  after 
sympathetic  stimulation  and  thus  increase  the  bulk  of  undifferen- 
tiated protoplasm. 

In  view  of  these  facts,  I  believe  that  von  Wittich's  and  Eck- 
hard's  experiments,  instead  of  proving  that  sympathetic  stimu- 
tion  can  not  possibly  be  due  to  compression  of  the  ducts  and 
alveoli,  demonstrates  that  it  must  be  due  to  such  compression  ; 
that  it  is  impossible  to  account  for  the  back  flow  on  any  other 
probable  hypothesis,  and  that  the  fact  that  the  saliva  does  not 
reach  its  former  level  is  readily  understood  by  reference  to  the 
nerve's  constrictor  action  and  the  temporary  vaso-dilation  ensuing 
on  breaking  simulation.  I  do  not  believe  that  von  Wittich  ever 
endeavored  to  analyze  in  detail  his  own  explanation,  or  he  must 
have  perceived  its  impossibility. 


328  MATHEWS. 

g.  The  Location  and  Nature  of  the  Contractile  Substance 

IN  the  Gland. 

The  contractile  tissue,  responsible  for  the  sympathetic  secre- 
tion, resides  neither  in  the  gland  capsule  nor  in  the  capillaries. 
Glands  dissected  free  from  the  capsules  secrete  normally.  The 
capillaries  cannot  be  held  responsible,  as  Vierheller  ''^  supposed, 
because,  as  one  may  readily  see  in  the  cat's  submaxillary,  the 
nerve  may  be  still  active  on  the  blood  vessels  while  producing 
no  secretion,  and  von  Wittich''^  records  that  after  curare,  the 
rabbit's  sympathetic  loses  its  secretory  activity  while  still  active 
on  the  blood  vessels  of  the  ear.  Unna^°  has  suggested  that  the 
basement  membrane  is  contractile,  and  this  may  possibly  be  the 
case.  There  is,  however,  no  evidence  of  it.  That  there  is 
smooth  muscle  about  some  of  the  principal  ducts  of  the  salivary 
glands  is  well-known,  but  most  histologists  have  failed  to  find 
any  between  or  about  the  alveoli.  However,  Pfliiger''"  and 
Schluter''''  have  each  described  isolated  fibres,  and  strands  of 
smooth  muscle  lying  between  the  alveoli,  distinct  from  the 
blood  vessels,  "so  that  the  stroma  is  not  entirely  lacking  in 
contractility." 

Whether  the  contractile  tissues  thus  far  recognized  histo- 
logically in  the  gland  are  those  active  in  the  production  of  this 
secretion  appears  to  be  doubtful.  The  physiological  evidence 
is  of  itself  so  strong,  however,  that  I  believe  we  can  safely  as- 
sume the  existence  of  such  a  tissue,  even  had  we  no  histolog- 
ical evidence  of  its  presence. 

Ji.  The  Changes  in  Gland  Cells  upon  Sympathetic  Stimu- 
lation. 

The  changes  in  gland  cells,  induced  by  stimulation  of  the 
sympathetic  nerve,  are  most  clearly  seen  in  the  rabbit's  parotid,**^ 
less  clearly  in  the  dog's  parotid,  where  the  nerve  causes  normally 
little  or  no  secretion.  The  changes  consist  in  the  diminution  in 
the  size  of  the  cell,  the  discharge  of  the  mucous  or  secretory 
products,  the  formation  of  new  undifferentiated  protoplasm  and 


SECRETION   PHYSIOLOGY.  329 

in  the  nucleus  becoming  round  and  moving  toward  the  center 
of  the  cell.  These  changes  are  identical  in  kind  with,  though 
taking  place  generally  more  slowly  than,  those  following  stimu- 
lation of  the  dilator  nerve  or  the  injection  of  pilocarpine.  Do 
they  indicate  the  direct  action  of  the  nerve  on  the  cell  ?  Al- 
though they  might  be  so  interpreted,  they  may  be  readily  under- 
stood without  any  such  assumption,  as  follows  :  Stimulation  of 
the  nerve  causes  a  compression  of  the  cells  and  thus  expels  from 
them  their  stored-up  metabolic  products  and  liquid.  By  this 
means  the  cells  discharge  their  products.  On  ceasing  stimula- 
tion the  alveoli  and  ducts  relax,  and  the  cells  take  up  water  and 
food  from  the  lymph.  The  latter  process  is  hastened  probably 
by  a  temporary  vaso-dilation  ensuing  when  the  sympathetic 
stimulation  is  broken.  In  virtue  of  the  food,  oxygen  and  lymph 
thus  brought  to  them  the  cells  form  new  undifferentiated  proto- 
plasm. On  several  successive  stimulations  the  accumulated 
metabolic  products  are  largely  discharged,  the  cells  become 
smaller  and  the  nuclei,  relieved  from  pressure,  become  round 
and  move  toward  the  center  of  the  cells.  The  same  explanation 
holds  also  for  the  changes  following  stimulation  of  the  dilator 
secretory  nerve,  with  the  exception  that  the  stored  products  are 
dissolved  out  of  the  cell,  instead  of  being  squeezed  out,  and  as 
vaso-dilation  accompanies  this  secretion  the  changes  take  place 
at  a  more  rapid  rate.  These  changes  are  discussed  more  at 
length  in  my  paper  on  the  Pancreas  Cell.* 

i.    Summary  and  Conclusion. 

The  phenomena  of  sympathetic  secretion,  which  have  been  con- 
sidered, could  hardly  indicate  more  clearly,  I  think,  the  muscular 
mechanism  of  that  secretion.  The  sudden  gush  of  saliva;  its 
sudden  cessation,  however  prolonged  the  stimulation  ;  the  dim- 
inution in  the  amount  of  saliva  secreted  when  the  stimulations 
are  rapidly  repeated  ;  the  apparent  paralysis  of  the  nerve  when 
the  ducts  are  empty  and  its  restoral  to  power  if  the  ducts  be 
passively  redistended  ;  the  augmentation  in  volume  of  the  secre- 
tion, when  the  ducts  are  abnormally  full  of  fluid  saliva,  and  the 

*  Shortly  to  appear  in  the  Journal  of  Morphology. 


330  MATHEWS. 

diminution  in  amount  of  secretion  when  there  is  little  saliva 
present ;  the  dependence  of  the  character  of  the  sympathetic 
saliva  upon  that  present  in  the  gland  at  the  moment  of  stimu- 
lation ;  the  back  flow  of  saliva  into  the  gland  on  stopping 
stimulation  when  the  gland  is  secreting  against  pressure ;  the 
presence  of  smooth  muscle  in  the  ducts  and  between  the  alveoli — 
these  facts  point  unmistakably  in  one  direction.  A  stronger 
chain  of  circumstantial  and  direct  evidence  that  this  secretion  is 
caused  by  compression  of  the  ducts  and  alveoli  by  contractile 
tissue  would  be  hard  to  imagine.  If  some  of  these  phenomena 
are  susceptible  of  explanation  upon  the  hypothesis  that  the 
secretion  is  due  to  gland  cell  activity,  others  of  them,  /.  c,  the 
augmented  salivary  secretion,  the  back  flow  of  saliva  on  break- 
ing stimulation,  the  paralysis  of  the  nerve  when  the  ducts  are 
empty,  and  its  restoral  to  power  if  the  ducts  be  redistended,  are 
explicable,  if  at  all,  by  that  theory,  only  by  means  of  improba- 
ble and  unproven  assumptions. 

The  surprisingly  ready  acceptance  of  the  Ludwig-Heidenhain 
theory  of  secretory  nerves,  acting  on  gland  cells,  as  an  explana- 
tion of  the  sympathetic  salivary  secretion  in  the  face  of  unmis- 
takable indications  of  a  muscular  mechanism,  has  been  due, 
largely,  I  believe,  to  the  generally  prevalent  belief  that  there  is 
but  one  mechanism  of  secretion.  That  this  belief  is  erroneous, 
there  has  long  been,  I  believe,  many  indications.  For  there  is 
direct  evidence  in  many  glands,  such  as  the  poison  glands  of 
snakes,  the  skin  glands  of  amphibia,  many  unicellular  glands, 
sebaceous  and  sweat  glands,  that  many  secretions  are  due  to 
muscular  action.  And  in  many  other  glands  the  phenomena  of 
secretion  have  shown  as  clearly  that  here  the  mechanism  was 
some  other  than  muscular.  There  must  evidently  be  at  least 
two  different  mechanisms,  a  muscular  and  some  other  one. 
Once  the  idea  that  there  is  but  one  mechanism  of  secretion  is 
abandoned,  the  salivary  secretions  will  be  found,  I  believe,  to 
lose  much  of  their  puzzling  character. 

The  facts  which  Heidenhain  urges  as  showing  that  the  sym- 
pathetic produces  secretion  by  action  on  the  gland  cell  are 
readily  accounted  for  if  the  sympathetic  cause  compression  of 
the  ducts  and  alveoli  and  vaso-constriction. 


SECRETION  PHYSIOLOGY.  331 

III.  OTHER  SECRETIONS  DUE  TO  MUSCLE 
ACTION. 

Probably  many  other  secretions  are  due  to  muscle  action.  ' 

The  unicellular  glands  of  the  carp-louse,  Argulus  foliaceus, 
are  surrounded  by  muscle  fibres.  Nussbaum,'"  observing  the  liv- 
ing glands,  states  that  they  are  emptied  by  the  contraction  of  this 
musculature.  Muscle  surrounds  the  unicellular  glands  in  the 
mantel  of  Aplysia,'^  and  the  glandular  pedicellaria  of  the  Echino- 
derms.'^^  The  gasteropod  liver*  possesses,  beneath  the  serosa, 
an  incomplete  musculature,  the  contraction  of  which  has  been 
watched  in  the  living  gland.  A  similar  sheath  is  found  in  the 
livers  of  Crustacea,  land  and  water  Isopods,  Amphipods  and 
Decapods."'* 

The  poison  glands  of  spiders  have  their  alveoli  enclosed  in  a 
tunic  of  spirally  arranged  muscular  fibres.^*  In  the  salivary 
glands  of  Cephalopods''^  the  cells  rest  on  connective  tissue,  which 
is,  in  turn,  surrounded  by  muscle  fibres.  An  examination  of  the 
physiology  of  these  glands  leaves  little  doubt  that  the  secretion  is 
due  to  muscular  action.^*  The  amphibian  skin  glands  are  sur- 
rounded by  a  muscular  sheath  lying  between  the  cells  and  the 
basement  membrane.  There  is  no  doubt  from  observations  on 
the  living  glands  (Engelmann,**^  Drasch,"  Ranvier''^)  that  this 
muscle  at  times  contracts,  compresses  the  gland  and  thus  causes 
a  secretion.  A  similar  muscular  mechanism  prevails  in  the 
mucous  glands  of  Petromyzon,  in  which  the  cells  are  bodily 
extruded. 

The  poison  glands  of  amphibia  and  reptilia  and  others  of  the 
salivary  glands'^"  are  provided  with  their  own  musculature,  or  are 
emptied  by  surrounding  skeletal  muscles.  Many  anal  and 
cloacal  glands,*'  sweat^^  and  sebaceous  glands  are  provided  with 
a  musculature  lying  between  the  basement  membrane  and  the 
cells.  There  is  little  doubt  that  the  secretion  of  sebum  is  pro- 
duced by  the  action  of  this  muscle.  The  same  can  be  said  for 
the  secretion  of  the  oil  gland  of  birds.  Probably  the  most  in- 
teresting secretion  due  to  muscular  action,  outside  of  the  sali- 
vary glands,  is  found  in  the  mammalian  sweat  glands.      From 


332  MATHEWS. 

the  observations  of  Ranvier,*"^  Joseph"^  and  others  certain  secre- 
tions of  sweat  are  probably  due  to  the  compression  of  the  gland 
by  this  muscle.  Probably  the  post-mortem  sweat  secretions, 
secretion  after  closing  the  artery,  or  the  injection  of  strychnia 
are  due  to  this  cause.  (There  is,  however,  a  second  sweat 
mechanism  associated  with  vaso-dilation.) 

Many  more  examples  of  the  muscular  mechanism  of  secretion 
might  be  given,  but  these  suffice  to  indicate  the  very  wide  dis- 
tribution of  such  a  mechanism.  Muscular  mechanisms  are,  pos- 
sibly, more  common  among  the  invertebrates,  but  they  play, 
also,  a  not  inconsiderable  part  in  vertebrate  secretions.  The 
vertebrate,  however,  with  its  delicately  coordinated,  closed  vas- 
cular system,  develops  a  second  mechanism,  that  of  osmosis, 
which  we  will  now  consider. 

IV.     SALIVARY  SECRETION  ENSUING  UPON  STIM- 
ULATION OF  THE  VASO-DILATOR  NERVE. 

That  the  general  features  of  chorda  secretion  coincide  with 
the  phenomena  of  osmosis,  regulated  by  the  nerve's  dilator  action, 
is  pointed  out  briefly  on  p.  356.  I  wish  here  to  consider  more 
particularly  those  facts  which  have  hitherto  been  irreconcilable 
with  such  a  theory,  and  have  been  generally  considered  evidence 
of  a  special  action  of  the  nerve  on  the  gland  cell.  These  facts 
are  the  most  important  evidences  of  a  secretory  nerves  and  so 
warrant  a  careful  consideration.  They  are  :  {a)  the  increase  in 
the  percentage  of  organic  solids  of  a  secretion  coincident  with  an 
increased  rate  of  secretion  ;  (1!^)  the  action  of  atropine  ;  {c)  the 
chorda-secretion  after  clamping  the  artery  ;  {d^  the  action  of 
nicotine. 

a.    The  Increase  in  the  Percentage  of  Organic  Constitu- 
ents COINCIDENT  with  AN  INCREASED  RaTE  OF  SeCRETION. 

Heidenhain  *  observed  that  on  passing  from  a  weak  to  a  strong 
stimulation  of  the  dilator  nerve  in  the  fresh  submaxillary  and 

*  Heidenhain.  Hermann's  Handbuch  der  Physiologie  V.  p.  50.  Studien  aus 
Breslan  IV,  1868,  p.   32. 


SECRETION  PHYSIOLOGY. 


333 


parotid  gland  of  the  dog,  not  only  was  the  rate  of  secretion  in- 
creased, but  also  the  percentage  of  solids.      He  obtained  a  simi- 


No.  of 

^§ 

Rate   of 

•~  1) 

Stimula- 

Time. 

Coil. 

f    01 

a  s 

<;  D 

Secretion 

Solids. 

Salts. 

5  B 

tion. 

in  I  min. 

6g. 

h. 

m.  m. 

I 

9 

20-45 

315—288 

3-5 

0.14 

0.74 

0.22 

0.52 

2 

9 

47-51 

160—130 

3-5 

.87 

2.10 

.56 

1^54 

3 

lO 

54-5-59 

100 —  60 

30 

.66 

2.08 

•45 

1.63 

4 

lO 

19-40 

264—245 

2.8 

.11 

1.44 

•36 

1.07 

5 

lO 

45-48 

160 — 130 

3-0 

1. 00 

I.41 

•49 

0.91 

6 

lO 

50-56 

80—  65 

3.0 

•50 

1. 16 

•39 

0.76 

7 

II 

9-27 

270 — 250 

2.5 

•13 

0.78 

•  30 

0.48 

8 

II 

30-34 

150 — 120 

3-1 

•77 

0.90 

•38 

0.51 

9 

II 

35-44 

80 —  30 

2.8 

31 

0.79 

•3b 

0.42 

lar  result  in  the  dog's  pancreas,  Gottlieb^^  in  the  rabbit's  pan- 
creas, and  Pawlow  and  Schumowa-Simanowskaja''^  in  the  dog's 
stomach.  In  the  sheep's  submaxillary,  on  the  other  hand,  there 
was  little  or  no  increase  in  the  per  cent,  of  solids  on  increasing  the 
stimulus. 

Heidenhain  believed  that  this  increase  in  solids  meant  that  the 
cerebal  nerve,  besides  quickening  the  flow  of  water  through  the 
cells,  rendered  the  cell  contents  more  soluble.  How  otherwise 
shall  we  explain  the  fact,  he  asks,  that  although  given  a  shorter 
time  of  contact  with  these  solids,  the  water  passing  through  the 
cells,  nevertheless  dissolves  more  than  during  slow  secretion. 
"  Die  blosse  Beriihrung  mit  der  aus  dem  Blute  ausgeschiedenen 
Fliissigkeit  ist  zur  Uberfuhrung  des  Schleimes  in  das  Secret 
nicht  ausreichend,  denn  sonst  musste  das  Secret  um  so  reicher 
daran  sein,  je  langer  die  Fliissigkeit  in  den  Driisenraumen  ver- 
weilt,  d.  h.  je  langsamer  die  Secretion  vor  sich  geht.""'  He 
further  assumes  that  the  trophic  fibers  require  a  stronger  stimu- 
lus than  the  secretory.  "  Das  cerebrale  Secret  wird,  so  lange 
die  Driise  unermiidet  ist,  bei  Reizverstarkung  reicher  an  or- 
ganischen  Bestandtheilen,  weil  der  Umsatz  der  organischen  Sub- 
stanzen  in  den  Zellen  unter  den  Einflusse  der  starker  gereizten 
trophischen  Fasern  schneller  steigt,  als  der  Wasserstrom  unter 
dem  Einflusse  der  starker  gereizten  secretorischen  Fasern."""* 


334  MATHEWS.   ' 

There  are  two  possible  fallacies  in  Heidenhain's  argument. 
One  fallacy  probably  lies  in  his  tacit  assumption  that  the  gland 
secretes  as  a  whole  ;  that  the  secretion  following  a  strong  stimu- 
lus is  derived  from  the  same  alveoli  as  the  secretion  following  a 
weak  stimulus.  The  other  fallacy  is  the  assumption  that  all  of 
the  organic  constituents  of  saliva  secreted  from  a  fresh  gland 
upon  a  strong  stimulus  are  in  solution.  The  true  reason  why 
the  dilator-secretory  nerve  may  cause  an  increase  in  the  organic 
matter  present  in  a  secretion,  coincident  with  an  increased  rate 
of  flow,  in  passing  from  a  weak  to  a  strong  stimulus,  may  be 
the  following  : 

If  a  very  weak  stimulus  be  used,  only  a  portion  of  the  alveoli 
are  aroused  to  activity.  The  supply  of  stored  up  products 
(hylogens)  in  these,  becomes  soon  exhausted  and  the  secre- 
tion derived  from  them  is  poor  in  organic  constituents.  On 
passing  to  a  strong  stimulus,  the  previously  resting  alveoli  are 
thrown  into  activity  and  the  secretion  derived  from  them  is  rich 
in  organic  constituents.  It  is  the  secretion  from  these  fresh 
alveoli,  which  increases  the  percentage  of  organic  constituents 
in  the  whole  secretion.  On  passing  from  a  long  continued 
weak  to  a  strong  stimulus  in  a  fresh  gland,  one  is  really  pass- 
ing from  an  exhausted  to  a  fresh  portion  of  the  gland. 

Moreover,  in  Heidenhain's  observation  there  is  a  second 
source  of  error  which  he  has  overlooked.  Heidenhain  treats  all 
of  the  organic  constituents  of  the  rapidly  secreted  saliva  as  if 
they  were  in  solution  and  considers  that  the  liquid  derived  from 
the  blood  is  in  contact  with  the  materials  to  be  dissolved,  only 
during  the  time  of  its  passage  through  the  cell.  There  .can  be 
little  question,  however,  that  saliva,  and  particularly  the  rapidly 
secreted  saliva  of  a  fresh  gland,  cannot  be  considered  a  true 
solution,  for  it  contains  many  bodies  in  suspension.  Heidenhain 
himself  has  been  one  of  those  to  describe  the  microscopical 
appearance  of  the  lumps  of  mucous  matter,  salivary  corpuscles 
and  occasional  leucocytes  found  in  this  secretion.  The  presence 
of  these  bodies  in  saliva  indicates  that  the  rapidly  secreted  saliva 
carries  out  of  the  cell  not  only  substances  in  solution,  but  vis- 
cous masses  of  mucous  matter  not  in  solution.     Its  swift  cur- 


SECRETION  PHYSIOLOGY.  335 

rent  is  able  to  transport  these  masses,  while  a  more  slowly 
flowing  secretion  is  not.  Furthermore,  in  all  probability  the 
saliva  keeps  on  dissolving  them  as  it  carries  them  along  and 
hence  becomes  actually  more  concentrated,  because  it  is  in  con- 
tact with  them  really  for  a  longer  time  than  the  more  slowly 
secreted  saliva  and  not  for  a  shorter  time  as  Heidenhain  thought. 
Heidenhain  made  no  endeavor  to  distinguish  between  the  mat- 
ters in  suspension  and  those  in  solution. 

That  any  gland  functions  as  a  whole,  as  Heidenhain  tacitly 
assumes  in  his  explanation,  can  not  be  maintained. 

The  whole  surface  of  the  stomach,  for  instance,  may  be  con- 
sidered as  one  large  gland.  It  has  long  been  known  that  se- 
cretion can  ensue  in  one  spot,  and  not  in  another.  Heidenhain 
himself,  has  called  special  attention  to  the  marked  differences  in 
the  condition  of  the  various  alveoli  in  the  salivary  glands.  Even 
in  the  resting  gland,  here  and  there  alveoli  will  be  found  posses- 
sing the  structural  features  of  secretory  activity."  In  the  stomach 
he  remarks  that  some  glands  show  changes  on  stimulation  before 
others,^^  and  I  have,  myself,  repeatedly  observed  glands  in  the 
Newt's  stomach  close  together  in  very  different  stages  of  activity. 
Kljhne  and  Lea^^  have  observed  this  in  the  living  rabbit's 
pancreas,  a  portion  only  of  the  gland  being  normally  active. 
After  pilocarpine  all  the  alveoli  passed  into  a  condition  of  activity. 
In  the  kidney  the  independence  of  the  various  tubules  in  se- 
cretion has  been  remarked  for  the  bird's  kidney  by  von  Wittich, 
and  for  the  mammalian  kidney  by  Ribbert,-*  and  by  Dr.  Herter 
in  conjunction  with  the  author.  Finally,  in  the  case  of  the  sali- 
vary glands,  Langley  says  that  even  on  prolonged  activity  of  the 
chorda  many  alveoli  show  no  change.  "  This  is  due,  in  some 
cases,  to  fibres  escaping  stimulation,  fibres  which  leave  the 
lingual  later  than  usual."  This  histological  evidence  appears 
to  me  to  be  conclusive  with  reference  to  the  idea  that  the  gland 
does  not  function  as  a  whole,  but  that  the  individual  alveoli  in 
the  secreting  gland  may  be  here  active,  there  passive. 

The  physiological  evidence  that  the  foregoing  is  the  true  ex- 
planation of  Heidenhain's  observation  is  hardly  less  conclusive. 
We    can  easily    obtain    evidence    that  the   secretion    obtained 


336  MATHEWS. 

during  a  weak  stimulus  is  derived  from  a  portion  of  the  gland 
only  in  the  following  manner  :  Let  us  stimulate  the  chorda  nerve 
carefully  with  a  very  weak  current,  until  a  large  amount  of  se- 
cretion has  been  obtained.  If  this  secretion  has  been  derived 
from  the  whole  gland  a  stronger  stimulus  should  yield  a  se- 
cretion much  less  concentrated  than  a  stimulus  of  equal  strength 
before  the  weak  stimulus.  The  glands  should  show,  in  other 
words,  a  considerable  exhaustion  of  the  gland  products.  If,  on 
the  contrary,  the  whole  of  this  secretion  has  been  derived  from 
a  portion  only  of  the  gland  the  rest  of  the  alveoli  must  remain 
practically  unaltered,  and  a  stronger  stimulus  arousing  these 
should  yield  a  juice,  little,  if  any,  poorer  in  organic  matters  than 
was  yielded  by  a  stronger  stimulus  before  the  weak. 

Werther''^  has  unintentionally  tried  this  experiment  and  found 
the  latter  possibility  to  be  what  actually  occurs.  A  very  weak 
stimulus,  with  the  secondary  coil  at  300—240  mm.,  was  em- 
ployed for  over  three  hours,  and  more  than  20  cc.  of  saliva 
were  secreted.  The  percentage  of  organic  solids  secreted  in  the 
slowly  flowing  saliva  steadily  fell,  but  the  percentage  of  such 
bodies  in  the  saliva  secreted  on  a  succeeding  stronger  stimulus 
was  little  if  any  less,  after  this  long  secretion,  than  it  was  with 
an  equally  strong  stimulus  before.  If,  however,  a  somewhat 
stronger  stimulus  was  employed,  the  secretion  from  a  still 
stronger  stimulus  was  much  poorer  in  organic  solids,  than  the 
similar  stimulus  before  the  weak. 

The  fact  that  rapidly  secreted  saliva  is  not  a  pure  solution, 
and  the  considerations  just  presented  concerning  the  independ- 
ence of  the  alveoli  of  the  gland  render  this  observatoin  of  Hei- 
denhain  of  doubtful  value  as  evidence  of  the  existence  of  se- 
cretory nerves. 

Moreover,  there  is  good  reason  for  doubting  the  truth  of 
Heidenhain's  statement,  in  the  quotation  on  page  333,  that  the 
liquid  derived  from  the  blood  is  incapable  of  dissolving  the  con- 
stituents of  the  cells  in  the  absence  of  nerve  influence.  As  has 
already  been  pointed  out,  in  treating  of  sympathetic  saliva, 
(page  322),  if  the  thin  chorda  saliva  be  simply  left  in  the  gland 
for  twenty  minutes,  or  more,  it  is  converted  into  a  dense,  vis- 


SECRETION  PHYSIOLOGY.  337 

cous  fluid  having  all  the  characteristics  of  sympathetic  saliva. 
This  conversion  takes  place  with  equal  readiness  whether  the 
gland  nerves  be  intact  or  divided. 

Heidenhain's  own  explanation,  also,  will  be  found  on  an- 
alysis, I  believe,  to  involve  such  assumptions  as  to  arouse  seri- 
ous doubt  of  its  truth.  To  explain  this  phenomenon  on  the 
basis  of  secretor}^  cell  activity,  he  assumed  separate  "trophic" 
nerve  fibers  acting  on  the  cells.  He  thus  necessitated  the  im- 
probable conclusion,  that  at  least  many  of  the  cells  of  the  sub- 
maxillary gland  received  at  least  four  different  nerve  ends,  /.  c, 
trophic  and  secretory  of  the  sympathetic,  and  trophic  and  secre- 
tory of  the  chorda  ;  and  at  least  two  entirely  different  nerve 
impulses,  /.  c,  trophic  and  secretory.  That  such  a  conse- 
quence should  not  have  aroused  suspicion  in  his  own  mind  of 
the  truth  of  his  explanation  is  difficult  to  understand. 

/'.     Post-mortem  Chorda    Salivary  Secretion. 

Another  strong  argument  that  the  chorda  does  not  produce 
its  secretion  by  its  dilator  action  on  the  blood  vessels,  but  by  di- 
rect action  on  the  gland  cell,  has  been  derived  from  the  so-called 
post-mortem  chorda  secretion.  Ludwig  and  Heidenhain  found 
that  if  the  gland's  artery  be  completely  closed,  or  if  the  head  be 
rapidly  cut  off,  and  the  chorda  at  once  stimulated,  a  fairly  copious 
secretion  ensued.  This  secretion  was  most  abundant  in  the  first 
minute  after  section,  and  thereafter  rapidly  diminished,  but  a  lit- 
tle could  still  be  obtained  four,  and  in  some  cases  five,  minutes 
after  decapitation,  or  compression  of  the  artery.  Thereafter  the 
nerve  was  ineffective.  Heidenhain  beheved  this  secretion  to  be 
due  to  the  action  of  the  nerve  on  the  gland  cell,  and  its  rapid  fail- 
ure to  lack  of  oxygen  and  water.  Both  Ludwig  and  Heidenhain 
believed  that  by  the  conditions  of  the  experiment  they  entirely 
eliminated  the  factor  of  the  nerve's  vaso-motor  action,  and  hence 
thought  it  demonstrative  evidence  that  the  secretory  and  dilator 
functions  of  the  nerve  were  independent. 

I  think  it  may  be  questioned,  however,  whether  the  condi- 
tions of  the  experiment  do  entirely  obviate  the  vaso-motor  action 
of  the  nerve,  and  whether  it  is  not  still  possible  that   this  dila- 


338  MATHEWS.  - 

tion  may  cause  the  secretion.  It  is  conceivable  that  this  post- 
mortem secretion  might  be  due  to  the  flow  of  blood  from  the 
veins  and  arterioles  into  the  capillaries,  owing  to  the  active  dila- 
tion of  the  latter  during  chorda  stimulation.  This  explanation, 
it  is  true,  necessitates  the  assumptions  that  the  chorda  tympani 
causes,  on  stimulation,  an  active  dilation  of  the  capillaries,  or 
veins,  as  well  as  of  the  arterioles,  and  that  that  dilation  in  some 
manner  makes  it  easier  for  the  liquid  to  pass  out  into  the  secre- 
tion. Both  of  these  assumptions  are  difficult  of  proof,  and  in 
the  limited  time  at  my  disposal  I  have  not  been  able  to  get 
demonstrative  evidence,  either  of  their  truth  or  error.  There  is 
some  reason  to  believe,  however,  that  they  may  possibly  be  true. 
That  liquid  passes  out  of  the  capillaries  into  the  secretion  of 
the  submaxillary  gland  because  of  an  attractive  pull  exerted 
upon  it  by  some  constituents  of  the  gland  cells,  has  been  sug- 
gested both  by  Ludwig  and  Heidenhain.  To  the  evidence  pre- 
sented in  favor  of  such  a  view  by  Heidenhain,  I  have  nothing  to 
add,  and  in  the  normal  condition  of  the  capillary  and  gland 
wall,  I  presume  that  the  hypothesis  is  true.  Ludwig  supposed 
that  during  chorda  stimulation  the  attractive  pull  of  the  cell  was 
increased,  owing  to  the  formation  of  substances  in  the  cell  pos- 
sessed of  a  higher  endosmotic  equivalent.  Heidenhain  believed 
that  the  attraction  of  the  cell  for  the  liquid  in  the  blood  was 
constant,  but  that  on  stimulating  the  chorda,  the  turgor  of  the 
cell  diminished  owing  to  the  passage  of  liquid  into  the  gland 
lumen,  and  water  was  thus  enabled  to  enter  the  cell  from  the 
blood.  Both  of  these  explanations,  as  will  be  noticed,  assume 
that  in  some  manner  the  effectiveness  of  the  attractive  pull  of 
the  cell  is  increased  during  nerve  stimulation  and  water  enters 
the  cells  independent  of  the  state  of  the  vascular  system.  The 
question  which  confronts  us  and  which  it  was  supposed  this 
post-mortem  secretion  settled  is  this  :  Does  stimulation  of  the 
nerve  cause  secretion  by  increasing  in  some  manner  the  attrac- 
tive pull  exerted  by  the  gland  cells  on  the  liquid  of  the  blood, 
or  does  it  indirectly  render  effective  by  vaso-dilation  an  attrac- 
tion which  is  constantly  exerted  by  the  cell  on  this  liquid  ? 
This    is   a  very    difficult    point   to    determine.     The    endeavor 


SECRETION  PHYSIOLOGY.  339 

has  been  made  to  answer  this  question  indirectly  by  showing 
that  vaso-dilation  may  ensue  without  secretion,  and  secretion 
without  vaso-dilation.  But  all  the  evidence  which  has  hitherto 
been  offered,  that  vaso-dilation  may  ensue  without  secretion, 
and  that  it  alone  is  incapable  of  causing  secretion,  is  invalidated 
by  the  fact  that  the  conditions  of  such  experiments  produce  an 
abnormal  gland,  or  capillary  wall,  both  factors  which  research 
on  lymph  formation  have  shown  to  be  of  importance.  Quinine, 
hydrochloric  acid,  sodium  carbonate,  or  atropine,  drugs  which 
enable  vaso-dilation  to  ensue  without  secretion,  probably  alter 
the  permeability  of  the  capillary,  or  gland  cell.  So  that  infer- 
ences can  be  drawn  from  such  experiments  as  to  processes  oc- 
curring in  the  normal  gland  only  with  the  greatest  caution.  The 
evidence  with  the  exception  of  the  post-mortem  secretion,  that 
the  chorda  may  cause  a  secretion  without  vaso-dilation  is  also 
unsatisfactory,  as  pointed  out  on  p.  355.  Attention  may  now  be 
directed,  hence,  to  this  post-mortem  chorda  secretion. 

It  is  probable  from  the  considerations  presented  on  page  l^'i, 
that  the  liquid  causing  this  secretion  is  derived  from  the  blood. 
Can  the  chorda  tympani  act  on  the  blood  vessels  in  the  absence 
of  circulation,  in  such  a  manner  as  to  facilitate  the  passage  of 
that  liquid  from  the  capillaries  to  the  gland  cells  ?  The  only 
possible  way  in  which  it  might  so  act,  I  believe,  is  by  causing 
an  active  dilation  of  the  capillaries  or  veins,  as  well  as  of  the 
arterioles.  Is  there  any  evidence  that  the  chorda  has  such  an 
action  ? 

Tiegerstedt'^"^'-  states  that  the  capillaries  are  contractile  but  that 
they  have  not  hitherto  been  shown  to  be  under  nerve  control. 
Roy  and  Brown  have  brought  forward  strong  evidence  that  the 
capillaries  are  normally  in  a  state  of  tonic  contraction  and  that 
they  may  actively  expand  independent  of  the  blood  pressure. 
They  observed  in  the  capillaries  of  the  web  of  the  frog's  foot 
that,  although  blood  pressure  might  be  diminished  almost  to 
atmospheric  pressure,  the  application  for  an  instant  of  chloroform 
to  the  web  caused  an  enormous  expansion  of  the  capillaries. 
Interesting,  also,  in  this  connection,  are  the  observations  of  von 
Frey.      v.  Frey^''  examined  microscopically  the  capillaries  of  the 


340  MATHEWS. 

frog's  tongue.  He  found  that  on  stimulation  of  the  dilator, 
hypoglossal  nerve,  a  dilation  of  the  capillaries  ensued  even  after 
the  blood  supply  had  been  cut  off.  If  the  artery  be  clamped, 
he  observed  that  the  blood  streamed  out  of  the  capillaries  both 
into  the  arteries  and  veins.  If,  now,  the  hypoglossal  be  stimu- 
lated the  capillaries  dilate  and  blood  streams  into  them  from  the 
arterioles  and  veins.  This  movement  persisted  for  from  one  to 
two  minutes  after  clamping  the  artery.  Furthermore,  in  ex- 
perimenting on  the  blood  flow  from  the  veins  of  the  submaxil- 
lary gland  of  the  dog  during  stimulation  of  the  chorda,  v.  Frey 
often  observed  that  stimulation  of  the  chorda  was  followed  by  a 
temporary  decrease  in  the  rate  of  flow  of  blood  from  the  vein, 
before  the  ordinary  increase.  He  suggests  that  this  would  seem 
to  indicate  a  widening  of  the  capillary  area  leading  to  a  back 
flow  of  blood  from  the  veins  were  it  not  more  probable  that  the 
increased  flow  from  the  dilated  arterioles  would  be  more  than 
sufficient  to  offset  this. 

These  facts  justify  the  conclusion,  I  believe,  that  on  stimu- 
lating the  chorda  tympani  in  the  severed  head,  the  capillaries  of 
the  gland  probably  dilate,  and  that  blood  enters  them  from  the 
veins. 

How  such  a  vaso-dilation  might  lead  to  a  secretion  is  not 
clear,  but  two  possibilities  suggest  themselves  :  (i)  that  the 
capillaries  are  thus  brought  into  closer  relation  with  the  alveoli, 
and  the  constant  attraction  exerted  by  the  gland  contents  for 
the  water  of  the  blood  is  thus  rendered  effective  ;  or  (2)  that 
vaso-dilation  may  in  some  way  increase  the  permeability  of  the 
capillary  wall.  The  post-mortem  chorda  secretion  can  not,  I 
believe,  be  accepted  unconditionally  as  illustrative  of  a  secre- 
tion independent  of  vaso-dilation,  until  these  possibilities  have 
been  shown  to  be  non-existent,  or  non-essential. 

If  it  shall  be  found  that  vaso-dilation  of  itself  is  a  cause  of 
secretion  in  the  normal  gland,  and  that  the  gland  cell  is  not  the 
secretory  agent,  the  facts  of  secretion  in  the  submaxillary  gland 
will  probably  necessitate  the  following  conclusions,  which  are 
not  without  interest  for  those  studying  the  physiology  of  the 
circulation:   (i)  That  stimulation  of  the   chorda  causes  an  ac- 


SECRETION  PHYSIOLOGY.  341 

tive  dilation  of  the  capillaries,  as  well  as  a  dilation  of  the  arte- 
rioles. (2)  That  the  sympathetic  is  able  to  overcome  the 
chorda's  action  on  the  arterioles,  but  not  its  action  on  the  capil- 
laries. This  is  shown  by  the  following  fact :  If,  during  strong 
stimulation  of  the  sympathetic,  the  chorda  be  irritated  by  a  cur- 
rent which  by  itself  is  barely  able  to  arouse  a  secretion,  a  secre- 
tion ensues  which  is  certainly  as  large,  if  not  somewhat  larger, 
than  the  chorda  alone  would  cause.  Such  a  weak  stimulus  of 
the  chorda  is,  however,  unable  to  neutralize  the  sympathetic's 
constrictor  action  on  the  arterioles,  as  shown  by  the  observa- 
tions of  v.  Frey.  It  will  be  necessary  to  assume,  hence,  that 
the  arterioles  have  remained  contracted,  while  the  capillaries 
have  dilated  and  blood  has  entered  them  from  the  veins  produc- 
ing a  secretion  analogous  to  the  post-mortem  chorda  secretion. 

I  endeavored,  in  a  variety  of  ways,  to  obviate  with  certainty 
all  possibility  of  the  chorda's  dilator  action.  By  the  injection 
of  supra-renal  extract  into  the  circulation  I  hoped  to  cause 
such  an  intense  peripheral  constriction  as  to  neutralize  the  di- 
lator action  of  the  nerve.  I  am  indebted  to  Dr.  R.  H.  Cunning- 
ham for  this  suggestion.  After  division  of  the  chorda  I  injected 
into  the  jugular  vein  the  whole  of  a  normal  salt  extract  of  two 
powdered  supra-renal  capsules  of  another  dog.  I  found,  how- 
ever, that  the  injection  was  followed  by  a  slow  constant  secre- 
tion of  what  appeared  to  be  sympathetic  saliva,  and  that  this 
secretion  Avas  increased  at  all  times  by  a  very  weak  stimulation 
of  the  chorda.  Indeed,  the  chorda  caused  a  larger  secretion 
after  the  injection  than  before,  probably  due  to  the  vaso- con- 
striction in  other  areas  of  the  vascular  system.  This  result  was 
so  discouraging  that  I  did  not  attempt  to  repeat  it. 

Heidenhain  remarks  that  large  doses  of  physostigmin  cause 
such  an  intense  constriction  of  the  arterioles  of  the  gland  after 
division  of  the  chorda  that  stimulation  of  the  latter  nerve  is  un- 
able to  cause  either  a  vaso-dilation,  or  secretion.  Unfortunately, 
Heidenhain  does  not  give  a  full  account  of  the  experiment. 
Were  it  true  that  the  drug  produces  this  effect  within  three  or 
four  minutes  of  its  injection,  it  would  be,  I  believe,  conclusive 
evidence  that  secretion  can  not  ensue  in  the  absence  of  vaso- 

Annals  N.  Y.  Acad.  Sci.,  XI,  September  13,  1898 — 23. 


342  MATHEWS. 

dilation,  and  that  the  nerve  does  not  cause  secretion  by.  action 
on  the  gland  cells  ;  for  it  is  known  that  the  drug  does  not 
directly  paralyze  the  hypothetical  secretory  fibers,  or  the  gland 
cell.  To  obtain  the  details  of  the  drug's  action,  I  injected  into 
the  jugular  vein  of  a  medium-sized  dog  o.  i  gr.  of  physostigmin 
sulphate.  But  although  the  chorda  was  divided,  a  spontaneous 
secretion  began  which  stimulation  of  the  chorda  considerably 
increased.  This  discrepancy  from  Heidenhain's  results  is  prob- 
ably due,  I  believe,  to  the  impure  calabar  extract  he  used. 

I  endeavored  to  ascertain  whether  the  presence  of  blood  in 
the  capillaries  was  an  essential  condition  of  the  post-mortem  se- 
cretion by  forcing  the  blood  out  with  air.  After  ligaturing  the 
carotid  artery  and  placing  in  it  a  canula  directed  headwards  I 
rapidly  cut  off  the  head  and  allowed  air  to  pass  into  the  carotid 
under  a  pressure  of  loo  mm.  of  Hg.  The  first  experiment  gave 
a  positive  result.  On  stimulating  the  chorda  a  brief,  scanty  se- 
cretion was  obtained  which  quickly  ceased.  Examination  of  the 
gland  showed  it  to  be  practically  bloodless.  In  two  other  simi- 
lar experiments  the  post-mortem  secretion  was  greatly  reduced 
in  amount  and  ceased  after  i  to  3  minutes,  instead  of  lasting  for 
from  3  to  5  minutes,  as  normally.  The  glands  in  these  experi- 
ments still  contained  blood  in  the  veins.  The  experiments  indi- 
cate, I  believe,  that  the  presence  of  blood  in  the  capillaries  is  an 
essential  condition  of  this  secretion.  I  regret  not  having  been 
able  to  bring  my  experiments  to  a  more  satisfactory  con- 
clusion, but  it  is  to  be  hoped  that  the  important  bearing  of  this 
post-mortem  saliva  upon  the  theory  of  secretion  may  lead  to 
its  being  made  the  subject  of  careful  investigation. 

From  the  following  experiments  the  following  conclusions 
may  be  drawn  relative  to  this  post-mortem  secretion  : 

I.  After  clamping  the  gland  artery,  or  cutting  off  the  head, 
a  secretion  may  be  obtained  from  the  submaxillary  gland  on  stim- 
ulating the  chorda.  This  secretion  is  most  abundant  in  the  first 
minutes,  and  thereafter  rapidly  diminishes.  After  four  or  five 
minutes  no  more  secretion  can  be  obtained.  The  total  amount 
of  saliva  secreted  varies  from  0.3  to  1.5  cc.  (Experiments 
XVIII,  XXII  and  LXIV.) 


SECRETION  PHYSIOLOGY.  343 

2.  If  the  gland  be  left  without  stimulation  for  a  minute  after 
decapitation  the  total  amount  of  saliva  obtainable  is  considerably- 
reduced. 

3.  If  the  gland  be  not  stimulated  until  3  or  4  minutes  have 
passed  a  small  secretion  may  be  obtained  6  minutes  after  decapi- 
tation.    (Experiment  XVIII.) 

4.  If  air  be  blown  into  the  carotid  artery,  after  cutting  off 
the  head,  the  secretion  of  saliva  is  reduced  in  amount  and  se- 
cretion ceases,  either  abruptly  or  after  2  to  3  minutes.  (Experi- 
ments LXIII,  LXVI  and  LXVII.) 

5.  If  defibrinated  blood  be  run  under  small  pressure  into  the 
vein  of  the  gland  a  small  secretion  may  be  obtained  20  to  30 
minutes  after  clamping  the  gland  artery. 

6.  If  the  blood  supply  be  cut  off  for  30  minutes,  on  read- 
mitting blood  the  arterioles  dilate,  arterial  colored  blood  issues 
from  the  vein  at  a  rapid  rate  and  a  spontaneous  secretion  begins. 
The  rate  of  this  secretion  is  not  changed  by  stimulation  of  the 
chorda  in  the  first  minute.     (Experiment  Va.) 

Experiment  Va. 

Large  dog.  3  cc.  i  %  morphine  sulph.  subcut.  Tracheot- 
omy. Ether.  Canuls  in  both  submaxillary  ducts.  Both 
chordo-linguals  and  both  sympathetics  cut.  The  left  vagus  sub- 
sequently divided  also.  The  right  gland  is  stimulated  from 
time  to  time.  See  p.  305.  The  left  is  freed  from  its  tunic  and 
is  attached  only  by  the  hilum.  The  vein  on  the  upper  surface  is 
open  and  flows  continuously.  The  only  blood  vessel  coming 
to  the  gland  is  the  hilum  artery.  The  other  artery  was  tied  and 
cut. 

Readings  computed  in  cc. 

Nerve.  Amount  of  Secretion  in  cc. 


Clamped  artery  going  to  gland. 

c  Gradually  less. 

c  None. 


Time. 

h 

m 

s        h 

3 

25 

3 

25 

~  3 

3 

30 

3 

32 

3 

35 

.07 


344  MATHEWS. 


3 

37 

s 

.00 

3 

40 

s 

.00 

Inject  5  cc.  .5%  NaCl  into  duct. 

3 

41 

S 

.05 

3 

42 

Undamped  artery. 

3 

43 

30 

c 

Active  secretion. 

3 

44 

Gland  secretions  spontaneously  .17  cc.  per  minute. 

Cut  left  vagus. 

4 

07 

30 

Clamped  artery  again. 

4 

07 

30 

-  4 

08 

Chorda  ( intermittent ) . 

•50 

4 

08 

-  4 

09 

c 

.18 

4 

09 

-  4 

II 

30 

c 

.07 

4 

12 

c 

.00 

4 

13 

-  4 

14 

S 

.08 

4 

15 

-  4 

17 

c-coil  12 

.00 

4 

17 

30 

-  4 

18 

15 

S 

.05   (very  viscid) 

4 

20 

s 

.00 

4 

23 

Inject  NaCl.  5%  into  duct. 

4 

24 

s  30  sec. 

.04 

4 

25 

c 

.00 

4 

26 

-  4 

27 

s 

.00 

4 

28 

Inject  y^,  cc.  fluid  into  duct, 
stimulation. 

Most  of  it  runs  out  before 

4 

29 

S 

.025 

4 

29 

30 

Unclamp  artery  (red  blood  rushes  out  of  vein). 

4 

30 

-  4 

31 

Gland  secretes  spontaneously. 

.1    cc. 

4 

31 

-  4 

32 

"            "                    " 

.12  cc. 

4 

33 

6 

c 

.30  CC.  per  minute. 

4 

35 

4 

32 

Spontaneously  secreting. 

.08  cc.  per  minute. 

4 

37 

-  4 

38 

c  I  mm. 

.7  cc. 

4 

38 

-  4 

45 

Spontaneously. 

■5  cc. 

4 

45 

c 

.9  cc.  per  minute. 

4 

45 

30 

Clamped  artery  again. 

4 

46 

30 

-  4 

47 

30 

c  (coil  12) 

•5 

Gland  still  slowly  secreting  spontaneously. 

4 

48 

30 

-  4 

49 

3" 

c 

.1 

4 

50 

-  4 

51 

c 

•03 

4 

51 

30 

-  4 

52 

30 

c 

.005  in  first  thirty  seconds, 
then  no  more. 

4 

53 

-  4 

54 

S 

.03 

4 

54 

-  4 

55 

c 

.00 

4 

■55 

30 

-  4 

56 

30 

c  coil  10 

.00 

4 

57 

-  4 

58 

s  coil  10 

.015 

5 

02 

Undamped  artery. 

5 

02 

30 

c 

Readily  secretes. 

Blood  rushes   continuously   out  of  vein  a  bright  red    on 
unclamping  the  artery. 
5     03  —  5     09  Gland  secretes  spontaneously  ._5  cc. 

5     09  -  5      10  s  .05 


SECRETION  PHYSIOLOGY.  345 

5     13     30  Clamped  artery. 

5     13     40  -  5     14     40                       c  .5 

5     14     40-5     17     30  No  stimulation. 

5     17     30  -  5     18     30                       c  .03 

5     19           -  5     20                               c  .02 

5     20                                                     c  .00 

5     22          -  5     23                             s  .01 

5     24                                                      c  .CO 

5     25           -  5     26                              s  .01 

5     35                                                   c  .00 

5     35     30                                       .      s  .00 

5     36                                    Undamped  artery.     Red  blood  rushes  from  tbe  vein. 

5     40                                    Chorda.  Rapid  secretion. 

Gland  secretes  spontaneously. 

5     45           -  5     46           Right  Sympathetic.  .1  cc. 

5     47           -  5     48           Left  Sympathetic.  .04  cc. 

Cut  off  head  as  rapidly  as  possible.     Was  unable  to  saw 

5     49     30                               through  the  vertebral  column.  All  the  muscles  and  skin 
severed. 

Right  gland. 
5     50     30-5     55  Intermittent  stimulation  of  right  chorda.  .530 

5     55  Chorda  (coil  5)  muscular  contractions.     No  secretion. 

5  57                                     Right  S}Tnpathetic.  .22  CC. 

6  10                                    Right  sympathetic.  .04  CC. 

^  Left  gland  ;   no  secretion  either  from  chorda  or  sympa- 

5     50  tjjgti^_ 


Experiment  LIV. 

Right  submaxillary.  Chorda  and  sympathetic  cut.  Dog 
under  morphine  and  ether.  Tracheotomy.  The  dog's  respira- 
tions become  very  slow,  and  finally  cease  without  any  struggles, 
and  without  ether.     There  was  considerable  fluid  in  the  trachea. 

4.46.  Stimulate  the  chorda  while  dying,  chorda  effective 
until  4.50.  The  secretion  becomes  less  and  less  and  finally 
ceases. 

I  then  stimulated  the  sympathetic  and  obtained  a  very  copious 
secretion  of  .  2  cc.      No  more  secretion  from  either  nerve. 

Experiment  LXIV. 

Before  cutting.      10  seconds  stim.      Coil  24.     Secretes  .79  cc. 
Begin  to  cut  at  4.50.      i  minute  to  sever  head   completely. 
No  secretion  during  operation. 


846  MATHEWS. 


h 

m 

s 

h      m 

4 

57 

- 

4     58 

Stimulates  3  times,  10  seconds  at  a  time. 

4 

59 

"                        10  seconds 

4 

59 

30 

"                        10     " 
No  more  secretion. 

Amount. 

.515  cc 
.150  cc. 
.021  cc. 


Total  time  of  stimulation  50  seconds.     Total  amount.  .686  cc. 

From  beginning  to  cut  to  end  of  chorda  effect,  3  m.  30  s. 

Experiment  XXI. 

Before  cutting.      Coil  20.      10  s.  stimulation  secretes  .55  cc. 
Begin  to  cut  at  4.05.      i  minute  to  sever  head  completely. 
No  secretion  during  operation. 


h 

m 

s 

h 

m 

Amount 

4 

06 

-  4 

07 

Stimulate  3  times,  10  seconds  at  a  time. 
Dog  swallows. 

I. 

2. 
3- 

.235 
.040 
.090 

4 

07 

-  4 

08 

"         3  times,  10  seconds  at  a  time. 
Swallows. 

I. 

2. 
3- 

.070 
.040 
.060 

4 

08 

15 

Coil  to  10,  muscular  contractions,  10  sec. 

.100 

4 

09 

30  seconds  stim.  off  and  on  (muscle). 

.030 

4 

09 

15 

No  more  secretion. 

4 

10 

Coil  4.    Heavy  contractions  (escape  of  current). 

000 

Total  time  of  stimulation,  85  seconds.     Total  amount, 

.665  cc 

Time  from  beginning    to   cut    until    end    of  chorda    effect, 
4  m.  15  s. 

Experiment  XVIII. 

Before  cutting.  Coil  11.  Stimulate  10  seconds. 
Right  gland  secretes  .64  cc.  Left  gland,  .61  cc. 
5.24.30  begin  to  cut  head.     Head  severed  in  30  s. 


h     m     s  h    m  RIGHT  gland.  Amount. 

•125 
.100 
.080 
.070 
.050 

3.  .020 

4.  .010 

5     27  -  5     28  "_      40  seconds.  .040  cc 

5     28     30  "         10       "  .000 


5     25  -  5     26         Stimulate  3  times,  lo  seconds  at  a  time. 

5     26  -  5     27  "        4     " 


SECRETION  PHYSIOLOGY.  347 

Left  Gland.  Amount. 

5     30                                  Stimulate  left  chorda  10  seconds.  .070 

next  10       "  .010 
5     30     30                                   <<        <<    chorda   (strong  muscular  contrac- 
tions). .070 

5  31  Left  chorda.     No  more  effect  except  on  mus- 

cular contraction. 

Summary. 
Right  gland. 

Total  time  of  stimulation,  120  seconds.     Total   secretion,    .495  cc.     From  be- 
ginning of  cut  to  end  of  chorda  effect,  4  minutes. 

Left  gland. 
Total  time  of  stimulation,  20  seconds.      Total  amount,  .080  cc.      Time  from  be- 
ginning to  cut  to  end  of  chorda  effect  (2)5  minutes,  30  seconds. 

Experiment  LXIV. 

Before  cutting.      Coil  18.     30  sec.  stimulation.     Secretes  2.1 
cc.      Cut  head  at  4.30,  1 1^  minutes  to  sever  completely. 

h     m      s        h     m 

4     31     40-4     36     Intermittent  stimulation.     Secretes  .250  cc. 

No  more  secretion  after  4.35. 
4     38  Stimulate  sympathetic  for  two  minutes,  secretes  .065  cc. 

Time  from  beginning  of  cut  to  end  of  chorda  effect  5  minutes. 

Experiment  XXII. 

Before   cutting.      Coil    18.    10    sec.   stim.      Secretes    .2   cc. 
Cut  at  6.07.      30  seconds  to  sever  head  completely. 

h     m       s         h     m       s 

4     07     30  -  6       9.  Stimulation,  1st   10  seconds  .225  cc. 

40  seconds  stim.  .060  cc. 

6  09     20-6     19     10     Stimulate  coil  18.   30  sec.  stim.  .150  cc. 
6     10     30                             Chorda  no  mre  effect 

6     12  Coil  to  14.     Muscular  contractions  .050  cc. 

Total  secretion  .375  cc. 

Time  from  cutting  till  chorda  ineffective,  3  m.  30  s. 

Experiment  LXIII. 

Small  dog,  Irish  terrier,  under  ether.      Canula  in  left  Whar- 
ton's duct.     Tracheotomy.      Chorda-lingual  nerve  cut.       Pro- 


348  •     MATHEWS. 

tected  electrodes  on  chorda.  Vago-sympathetic  not  cut.  Can- 
ula  connected  with  air  reservoir  in  the  head  end  of  the  left 
carotid  artery. 

Before  cutting,  stimulation  of  the  chorda,  with  secondary  coil 
at  200,  causes  a  secretion  of  0.15  cc.  in  10  seconds. 

Head  rapidly  severed  at  4.17  P.  M.  As  soon  as  it  was 
severed  I  opened  the  cock,  letting  air  into  the  carotid.  I  then 
stimulated  the  chorda  tympani  at  4.18.  Stimulation  of  the 
chorda  causes  a  secretion  of  .02  cc.  Secretion  then  stops 
and  no  more  can  be  obtained  by  any  strength  of  stimulus. 

Experiment  LXVI. 

Conditions  of  the  experiment  as  in  Experiment  LXIII.  Be- 
fore cutting  off  the  head  stimulation  of  the  chorda  for  10  seconds 
with  secondary  coil  at  180  causes  a  secretion  of  .17  cc. 

Head  rapidly  severed  from  body  at  3.03.  Chorda  stim- 
ulated at  3.03.45  for  20  seconds.  Gland  secretes  .20  cc. 
Air  then  forced  into  the  carotid  artery. 

3.04.30—3.05.30  stimulation  of  the  chorda  with  secondary 
coil  at  130  causes  .07  cc.  Thereafter  no  secretion  with  a  stim- 
ulation of  any  strength. 

Experiment  LXVII. 

Conditions  of  experiment  the  same  as  in  Experiment  LXHI. 
Before  decapitation  stimulation  of  the  chorda  for  10  seconds 
with  secondary  coil  at  230  yields  a  secretion  of  0.2  cc. 

Dog  decapitated  at  10.49.  ^i^  forced  into  carotid'  as  soon 
as  cutting  began.      Head  severed  in  30  seconds. 


h. 

m. 

s. 

10 

49 

45 

Chorda 

10  seconds. 

Coil  230 

0.1  cc. 

10 

50 

30 

" 

"         " 

"     200 

0.05 

10 

52 

" 

20        " 

"    180 

0.05 

Thereafter  no  more  secretion. 

Post-mortem  examination  shows  the  gland  veins  to  be  filled 
with  blood.  The  air  does  not  seem  to  have  penetrated  the 
gland. 


SECRETION  PHYSIOLOGY.  349 

c.     The  Nature  of  the  Action  of  Atropine  and 
Pilocarpine. 

Atropine  permits  vaso-dilation,  on  stimulation  of  the  chorda, 
but  prevents  secretion.  The  drug  has  been  supposed  to  act, 
not  on  the  gland  cell,  but  on  the  ends  of  the  secretory  nerve 
fibers.  The  reasoning  for  this  is  as  follows  :  In  the  dog's  sub- 
maxillary, atropine  paralyzes  the  chorda  secretion,  but  not  the 
sympathetic.  If  the  sympathetic  innervate  the  gland  cell  and 
cause  its  secretion  by  action  on  the  latter,  the  gland  cells  con- 
nected with  this  nerve  have  evidently  not  been  paralyzed.  As 
there  is  no  reason  to  suppose  these  cells  different  from  those 
connected  with  the  chorda,  it  is  probable  that  the  cells  con- 
nected with  the  chorda  have  not  been  paralyzed.  But  if  the 
gland  cells  have  not  been  paralyzed,  and  the  dilator  action  of 
the  nerve  remains  unaffected,  we  must  assume  that  there  is  some 
third  element  connected  with  the  nerve  which  has  been  para- 
lyzed. This  must  be  the  element  causing  secretion,  /.  t'.,  the 
secretory  nerve  fiber.  The  latter  must  be  paralyzed  at  the  nerve 
termination,  since,  as  far  as  known,  atropine  does  not  act  on  the 
nerve  fibre.  This  argument  is  true  only  for  the  dog  and  not 
for  the  cat^'  since,  in  the  cat,  atropine  paralyzes  the  sympathetic 
as  well  as  the  chorda.  The  argument,  as  will  be  seen,  depends 
on  the  assumption  that  the  sympathetic  causes  secretion  by 
action  on  the  gland  cells.  This,  as  pointed  out,  is  probably  in- 
correct. The  sympathetic  produces  its  secretion  by  action  on 
contractile  tissue.  There '  is,  hence,  no  longer  any  reason  to 
suppose  that  the  gland  cells  have  not  been  paralyzed  by  the 
drug.  How  it  acts  upon  the  cell  is  unknown,  but  the  effect  of 
that  action  is  to  prevent  or  diminish  the  passage  of  fluid  through 
the  cells.  The  variation  in  the  susceptibility  to  its  action  of  dif- 
ferent glands  in  the  same  animal  (compare  the  pancreas,  salivary 
glands  and  kidneys  of  dog),  or  of  the  same  gland  in  different 
animals  (compare  the  pancreas  of  the  dog  and  rabbit)  points,  I 
believe,  toward  an  action  on  the  gland  cell  itself,  the  variations 
in  its  action  being  due  to  variation  in  the  chemical  composition 
of  the  cells. 

THEOLOGICAL    SEMINARY. 


350  MATHEWS. 

That  atropine  does  act  on  the  gland  cell  is,  perhaps,  indicated 
also  by  the  action  of  its  great  antagonist  pilocarpine.  Pilocar- 
pine, namely,  produces  a  secretion  of  sweat  two  to  three  weeks 
after  cutting  the  sciatic  of  the  cat,  when  the  nerve  is  totally  in- 
active.''^ ^^  ^^  Luchsinger,*''  in  commenting  on  this,  says  that 
this  secretion  must  be  due  either  (i)  to  action  on  the  secretory 
cells  themselves,  or  (2)  to  the  non-degeneration  of  the  nerve 
ends.  The  second  possibility  is  impossible  since  these  nerve 
ends  are  not  provided  with  nuclei.  A  similar  secretion  may  be 
obtained  in  the  dog's  salivary  glands,  fourteen  days  after  cut- 
ting both  chorda  and  sympathetic.  The  evidence  is  here  not  so 
conclusive  since  the  submaxillary  ganglion  does  not  degenerate. 
In  the  sweat  secretion,  however,  I  believe  the  evidence  is  fairly 
strong  that  pilocarpine  does  act  directly  on  the  gland  cell.  It 
thus  strengthens  the  evidence  that  atropine  also  acts  on  the  cell. 

There  is  also  reason  for  believing  that  atropine  acts  in  some 
manner  on  the  capillary  wall,  thus  reducing,  or  preventing  the 
transudation  of  lymph.  It  might,  in  this  way  effect  secretion 
from  glands.  This  possibility  has  not  received  the  attention  it 
deserves.* 

The  evidence  that  atropine  checks  lymph  transudation  is  as 
follows  : 

If  atropine  permitted  the  transudation  of  lymph  normally  en- 
suing on  vaso-dilation,  it  would  be  expected  that,  after  its  injec- 
tion, stimulation  of  the  chorda  would  render  the  submaxillary 
gland  oedematous,  since  fluid  no  longer  passes  into  the  secre- 
tion. Quite  the  contrary  is  the  fact.  I  have  repeatedly  stimu- 
lated the  gland  all  day,  after  the  injection  of  atropine,  without 
producing  a  trace  of  oedema.  Heidenhain  ^■''  himself  says  : 
"  After  atropine  on  stimulation  of  the  chorda  tympani  no  in- 

*  Heidenhain's  reasons  for  rejecting  the  possibility  that  atropine  checks  lymph 
transudation  and  thus  secretion  will  be  found  in  Hermann's  Handbuch.  A  strik- 
ing instance  of  failure  to  consider  this  possibility  is  the  following  quotation  from 
Larigley : 

"Atropine  prevents  the  stimulation  of  the  hilum  from  producing  a  secretion. 
Nicotine  does  not  do  this,  therefore,  atropine  acts  upon  structures  more  peripheral 
than  those  acted  upon  by  the  nicotine.  Since  nicotine  acts  on  nerve  cells,  and 
atropine  does  not  act  on  gland  cells,  atropine  must  produce  its  paralyzing  result  by 
action  on  the  secretory  nerve  endings." 


SECRETION  PHYSIOLOGY.  351 

crease  in  lymph  flow  occurs,  even  when  during  stimulation  of 
the  chorda  the  medulla  is  stimulated  and  the  blood  pressure 
greatly  increased."  Brunton  in  commenting  on  this  says : 
"  It  appears  to  me  that  this  circumstance  can  hardly  be  explained 
otherwise  than  by  supposing  that  atropin  not  only  paralyses  the 
secretary  fibres  of  the  chorda,  but  acts  upon  the  blood  vessels 
in  such  a  manner  as  to  greatly  diminish  or  prevent  the  exuda- 
tion which  would  usually  take  place  from  them  into  the  lymph 
spaces." 

Heidenhain^^  supposed  that  lymph  normally  left  the  blood 
vessels  on  account  of  the  secretory  pull  exerted  by  the  gland 
cell.  Atropine  prevented  lymph  transudation  by  paralysis  of 
the  secretory  chorda  nerve  ends.  He  was  led  to  this  conclusion 
chiefly  by  the  following  facts  :  (i)  No  more  lymph  normally 
leaves  the  blood  vessels  than  passes  into  the  secretion,  and  (2) 
if  one  inject  4.9%  solution  of  sodium  carbonate,  0.5%  hydro- 
chloric acid  or  quinine  sulphate  into  Wharton's  duct  the  chorda's 
secretory  power  is  annihilated,  but  on  stimulation  the  gland 
becomes  highly  oedematous.  If,  however,  atropine  be  injected 
into  the  blood  before  the  chorda  is  stimulated  and  after  the  in- 
jection of  quinine  into  the  duct  no  oedema  ensues,  however  long 
the  nerve  be  stimulated.  I  have  fully  confirmed  these  observa- 
tions. The  most  probable  interpretation  of  these  facts,  it  seems 
to  me,  is  that  quinine  prevents  the  passage  of  fluid  through  the 
glands  by  action  on  the  gland  cells,  but  does  not  prevent  lymph 
transudation.  That  atropine,  however,  acts  directly  on  the 
capillary  wall,  as  well  as  upon  the  gland  cell,  in  such  fashion  as 
to  prevent  lymph  transudation  and  secretion. 

A  further  indication  that  atropine  checks  lymph  transudation  is 
the  diminution  in  thoracic  lymph  flow  after  its  injection.  Tschir- 
winsky^®  found  that  in  morphinized  animals  thoracic  lymph 
flow  fell  from  3,75  cc.  to  1.5  cc.  and  from  10  cc.  to  4.2  cc.  in  a 
given  time.  Atropine  neutralized,  also,  the  increased  flow  due 
to  curare.  In  the  latter  case  it  fell  from  9  and  10  cc.  to  2.5 
and  5.3  cc.  in  a  given  time.  As  there  is  reason  to  believe 
(Adami)  that  curare  increases  lymph  transudation  by  direct 
action  on  the  capillary  wall,  the  inhibiting  action  of  atropine  may 


352 


MATHEWS. 


be  referred  to  an  opposite  action  on  the  same  structure.  Not 
knowing  of  Tschirwinsky's  work,  I  had  already  performed  simi- 
lar experiments  on  the  lymph  flow,  comparing  it  with  pancreatic 
flow  on  vagus  stimulation  and  after  pilocarpine.  I  found  (Ex- 
periment V  that  atropine  temporarily  neutralizes  the  large 
increase  in  lymph  flow  which  occurs  concomitant  with  increased 
panceas  secretion  during  rythmic  stimulation  of  the  vago-sym- 
pathetic  after  division  of  the  cervical  cord,  and  also  neutralizes 
the  increased  lymph  flow  due  to  pilocarpine. 


Experiment  Vb. 

Medium-sized  dog.  Ether.  Temporary  pancreatic  fistula. 
Tracheotomy.  Cervical  cord  cut.  Artificial  respiration.  Tho- 
racic duct  prepared.  Lymphatics  of  head  and  neck  ligatured. 
Readings  every  minute  in  cubic  centimeters  : 


Thoracic  Duct 

Pancreas. 

Thoracic. 

Pancreas. 

Th 

oracic. 

Pancreas. 

Vagi 

uncut. 

.050 

.009 

.197 

.009 

.220 

.02 

.110 

.013 

.180 

.004 

.220 

.02 

.115 

.012 

.180 

.008 

.200 

.02 

y^  hour  interval. 

.150 

— 

.200 

.015 

.120 

.013 

.190 

.006 

.180 

•015 

.119 

.012 

Rt. 

Vagus. 

Ryth. 

Coil  9. 

.180 

.010 

.090 

.009 

.200 

.000 

.190 

•015 

.130 

.Oil 

.180 

.000 

.160 

.013 

.120 

.010 

.100 

.002 

.180 

.017 

.110 

.010 

.300 

.068 

•155 

.017 

.100 

.008 

— 

•025 

■155 

.018 

.100 

.009 

— 

.015 

.170 

.015 

.102 

.004 

— 

■015 

Cut  vagi 

in  neck. 

.100 

— 

Off. 

.280 

.015 

Clot. 

.160 

.020 

.220 

.010 

I  shock 

per 

second. 

.140 

.010 

.160 

.005 

Rt.  Vagus. 

Ryth. 

Coil  10. 

■150 

.005 

.100 

.003 

.150 

.009 

— 

.010 

.120 

.007 

.220 

.006 

Rt. 

Vagus. 

Ryth. 

Coil  9. 

.100 

.009 

.250 

.010 

.360 

.006 

.100 

.010 

.170 

.005 

.200 

.009 

.060 

.015 

.230 

.010 

.240 

.005 

.050 

.020 

Current  ofi 

Coil  to  4. 

.090 

.010 

.200 

.005 

.200 

.005 

.120 

.015 

.190 

.007 

— 

.008 

.120 

.003 

.220 

.007 

Off. 

.120 

.007 

220 

.005 

Clot. 

0.15 

.065 

.010 

.310 

.002 

'•■ 

.011 

•125 

.010 

.210 

.001 

Left  Vagus 

Ryth. 

Coil  9. 

.100 

.oil 

.180 

— 

•550 

.030 

SECRETION  PHYSIOLOGY. 


353 


Thoracic. 

Pancreas. 

Thoracic.     ' 

Pancreas. 

Thoracic. 

Pancreas. 

.290 

.005 

.120 

.005 

.270 

.015 

— 

.005 

— 

.010 

— 

.005 

— 

.005 

•175 

.025 

.230 

.005 

— 

.010 

•225 

■  045 

.240 

.000 

Coil  to 

6 

.015 

.250 

.055 

—   suddenly 

.120 



.060 

.220 

.110 

.250 

.080 

— 

.090 

— 

.120 

Inject  .5 

cc.  atrop 

n  into 

.240 

.100 

.320 

.140 

supra-scap.  vein 



.090 

.300 

.130 

Stimulation  continued. 

Off.     Then 

on  by  accident. 

Off. 

.250 

.050 

.230 

.060 

— 

•115 

.200 

.070 

Off. 

.170 

.065 

— 

.030 

.140 

•035 

.200 

.030 

.180 

:o20 

.170 

.030 

.150 

— 

.140 

.015 

.160 

.030 

.200 

.030 

•145 

.015 

.120 

.015 

— 

.020 

•155 

.015 

.170 

.015 

— 

.015 

.110 

.OJO 

.130 

— 

.140 

.015 

.120 

.015 

.170 
Left  Vagus. 

Ryth. 

.010 
Coil  6. 

.140 
•145 

.010 
.016 

.120 

Off. 

.007 
.008 

.140 

.007 

•135 

.009 

.130 
■5  c 
.080 
.040 

.010 

.130 
.060 
.140 

.002 
.009 
.090 

.130                   .005 
.160                   .017 
Left     Vagus.       Rythmical. 

:.  atropin 

.010 
.010 

.200 
.290 

.120 
.130 
.140 

.160 
.250 
.210 

.002 
.008 
.000 

.090 
.100 
.100 

.005 
.007 
.008 

.235 

.110 

.240 

.001 

.120 

.100 
.100 

.012 

.280 
.235 

.130 
.130 

300 

.015 
.075 

.007 
.005 

.250 

.080 

.300 

.035 

Off 

.210 

.045 

.  no 

.005 
.006 

.340 

.210 
.190 

.154 

.116 

.052 

.350 
.300 

.too 

.100 

ito 

Stim.  Left  Vagus. 
.070 
.100 

Coil  6. 

.010 

.C08 

.160 
.190 
.190 
.170 

■043 
.020 
.020 
.025 
.011 

Left  Vagus 
.220 
.280 

Ryth. 
Off 

.140 

Coil  6. 
110 
.070 

.120 
.160 
.160 
.230 
.200 

.002 
.000 
.000 
.000 

— 

.014 

.200 

.070 

.260 

.000 

•15s 

.oi5 

.200 

.050 

.170 
.200 

.000 

.150 

.010 
.010 

.230 
.180 

.020 
.025 

Off. 

.000 

.150 

— 

.180 

.030 

.250 

.000 

Left  Vagus 

Ryth. 

Coil  6. 

•155' 

.005 

.170 

.000 

.210 

.010 

•145 

.005 

.190 

.000 

.190 

.000 

Left  Vagus 

.  Ryth 

Coil  6. 

This  experiment  is  of  interest,  not  only  as  a  clear  confirmation  of  Pawlow  and 
Mett,  but  because  of  the  invariable  increase  in  thoracic  lymph  flow  occun-ing  on 
stimulation  of  the  vagus.  I  have  repeatedly  sought  to  obtain  other  experiments  like 
it,  but  never  with  such  success.  The  operation  is  long  and  .apt  to  miscaiTy  at  some 
point. 


354 


MA  THEWS. 


Experiment  XI. 

Dog,  etherized.  Canula  in  thoracic  duct.  Readings  in  cc. 
every  minute. 

Thoracic  duct. 

.150,  .220,  .200,  .180,  .300,  .230,  .250. 

I  cc.  I  %  pilocarpine  into  left  femoral  vein.     Dog  perfectly  quiet. 

.250, .300,  .500,  .600,  .400,  .460,  .400. 

1  cc.  pilocarpine. 

.490,  .410. 

I  cc.  \fo  atropine  l%. 

.240,  .090,  .060,  .070, .170,  .110,  .120,  .090,  .090. 

Moved  head. 

.220. 

I  cc.  atropin. 

.130, .100,  .070, .060, .040,  .120. 

2  cc.  pilocarpine. 
.100,  .080,  .120,  .130. 

I  hour  interval. 
.160. 

It  is  not  without  interest  in  this  connection  that  pilocarpine, 
contrary  to  atropine,  increases  lymph  flow.  This  was  first  ob- 
served by  Tschirwinsky.''^  My  own  experiments  have  yielded 
a  positive  result  generally,  but  not  invariably.  In  all  cases  the 
dogs  had  divided  cervical  cords,  and  generally  divided  vagi. 
They  were  all  under  artifical  respiration.  The  lymph  was 
measured  in  cc.  for  equal  intervals  of  time. 


Experiment. 

Before  pilocarpine 
injection. 

After  the  injection 
of  1-2  cgs.  of  pilo- 
carpine. 

Remarks. 

II 

29 

14 

4 

62 

1.53 
2.44 
0.50 

1-55 
1. 41 

3.00 
6.09 
1.72 
10.40 
1.69 

7  minutes.     Dog  motionless. 

Some  movements  of 
abdomen. 

Motionless.      9  minutes. 

Movements. 

No  movements.     Pancreas 
did  not  secrete  either. 

In  experiments  1 1  and  1 4  there  were  no  visible  movements. 
The  flow  of  the  seven  minutes  after  injection  in  No.  1 1  was 


SECRETION  PHYSIOLOGY.  355 

double  that  of  seven  minutes  before,  and  in  experiment  14  was 
three  times  as  great.  In  experiment  62,  however,  there  was 
scarcely  any  difference. 

The  evidence  presented  in  the  foregoing  pages,  if  not  conclu- 
sive, certainly  indicates  that  atropine  restricts  and  pilocarpine 
increases  lymph  transudation.  They  may  in  this  manner  affect 
secretions.  In  any  case,  if  the  sympathetic  causes  its  secretion 
by  action  on  contractile  tissue  in  the  gland,  there  is  no  longer 
any  reason  against  assuming  that  atropin  acts  directly  on  the 
gland  cell,  in  such  manner  as  to  check  the  passage  of  fluid 
through  it,  and  thus  to  prevent  secretion. 

d.     The  Action  of  Quinine  and  Nicotine. 

We  have  considered  the  three  main  objections  which  have 
been  raised  against  the  chorda  salivary  secretion  being  an  osmosis. 
There  are,  also,  certain  other  phenomena  which  have  been 
thought  indicative  of  the  independence  of  the  secretory  and  di- 
lator action  of  this  nerve,  and,  hence,  are  worthy  of  a  short 
criticism. 

The  first  is  the  action  of  quinine,  which  when  injected  into 
the  gland  duct  causes  a  temporary  vaso-dilation,  but  no  secre- 
tion. If,  however,  the  chorda  be  stimulated,  still  greater  dila- 
tion ensues  and  secretion  takes  place.  This  secretion  is  less  than 
normal.  Heidenhain^^  interprets  this  to  mean  that  vaso-dila- 
tion cannot  of  itself  produce  a  secretion,  but  that  the  secretory 
fibres  must  be  aroused.  (See  literature  reference  No.  21,  p.  85. 
Also  reference  No.  23,  p.  45,) 

The  facts  may,  however,  be  otherwise  understood.  Quinine 
prevents  the  passage  of  liquid  through  the  gland  cell.  This  is 
shown  by  the  fact  that  ultimately  it  prevents  chorda  secretion, 
even  though  the  gland  become  oedematous.  If  the  permea- 
bility of  the  gland  membrane  be  thus  diminished,  the  slight 
vaso-dilation  caused  by  the  drug  may  be  insufficient  to  cause  a 
secretion,  whereas  a  larger  vaso-dilation  on  stimulating  the 
chorda  might  overcome  this  resistance.  Another  possibility  is 
that  the  quinine  reaches  a  portion  only  of  the  alveoli,  poisons 
these,  and  throws  their  capillaries  and  arterioles'  into  dilation. 


356  MATHEWS. 

On  stimulating  the  chorda  the  secretion  may  be  derived  from 
unpoisoned  alveoli  of  which  the  blood  vessels  have  not  hitherto 
been  in  dilation. 

The  value  of  Langley's  and  Heidenhain's  observation,  that 
the  secretory  fibres  of  the  chorda  tympani  recover,  after  nico- 
tine poisoning,  before  the  dilator  fibres,- is  seriously  impaired  by 
a  defective  method  of  determining  whether  vaso-dilation  did,  or 
"did  not,  occur.  If  we  admit  that  the  rate  of  flow  of  blood  from 
the  gland's  vein  is  a  criterion  by  which  we  can  determine 
whether  vaso-dilation  has  or  has  not  occurred  their  conclusion 
is  justified.  But  reflection  shows  that  if  vaso-dilation  be  slight 
the  amount  of  water  passing  out  into  the  secretion  might  so  re- 
duce the  bulk  of  blood  flowing  through  the  gland  as  to  mask 
entirely  all  effects  of  the  increased  flow  due  to  vaso-dilation. 
In  fact,  the  flow  of  blood  from  the  vein  would  be  a  safe  cri- 
terion of  dilation,  only  if  there  were  no  escape  of  liquid  through 
the  capillary  wall,  a  condition  which  manifestly  does  not  here 
exist.  Langley's  and  Heidenhain's  conclusion  that  the  secre- 
tory function  recovers  before  the  dilator  is,  hence,  unjustified. 
The  same  criticism  applies,  also,  to  Heidenhain's  observation 
that  after  the  chorda  tympani  has  been  cut  and  allowed  to  de- 
generate for  three  or  four  days  stimulation  still  causes  an  in- 
crease in  the  paralytic  secretion,  but  no  increase  in  blood-flow 
from  the  vein. 

e.   Evidence  of    the  Osmotic    Character  of  the  Salivary 
Secretions  which  are  Accompanied  by  Vaso-dilation. 

wish  now  to  summarize  briefly  those  features  of  secretions, 
accompanied  by  vaso-dilation,  which  indicate  that  they  are  of  an 
osmotic  character. 

(i)  In  structure  the  salivary  glands  have  all  the  require- 
ments of  an  elaborate  osmotic  mechanism  They  are,  essentially, 
extraordinarily  thin -walled  bags,  possessing  an  enormous  sur- 
face, containing  a  mass  of  hydroscopic  indiffusible  substances. 
The  outer  surface  of  this  bag  is  in  intimate  association  with  a 
mesh  work  of  capillaries  so  coordinated  by  the  nervous  system 
as  to  permit  an  almost  instantaneous  flooding  of  the  gland  mem- 


SECRETION  PHYSIOLOGY.  357 

brane.      Plainly  here  are  all  the  requisites  of  a  delicate  osmotic 
mechanism  adapted  to  the  most  rapid  osmosis. 

(2)  Chorda  secretion  is  closely  dependent  on  blood  supply. 
(Compare  p.  342.)  Heidenhain  has  shown  that  partial  occlusion 
of  the  artery  diminishes  the  rate  of  secretion  (p.  88,  Breslau 
Studien  IV.) 

(3)  If  the  osmotic  equivalent  of  the  blood  be  increased  by  the 
injection  of  strong  salt  solutions  the  secretion  is  diminished   or " 
altogether  inhibited. ^^  ^'^ 

(4)  If  the  osmotic  equivalent  of  the  blood  be  decreased  by  the 
injection  of  water  the  rate  of  secretion  is  increased. '^'^ 

(5)  The  rate  of  secretion  is  increased,  other  things  equal,  by 
an  increase  in  the  rate  of  blood  flow  through  the  gland.'^*^  ^'^ 

(6)  The  rate  of  secretion  diminishes  when  the  hj/logens  are 
washed  out  of  the  gland.  (Paralytic  secretions,  secretion  after 
long  stimulation.)"^ 

(7)  Substances  may  be  absorbed  with  extraordinary  rapidity 
when  injected  into  the  duct  (nicotine,  atropine). 

(8)  If  the  percentage  of  salts  in  the  blood  be  increased  the  per- 
centage of  salts  in  the  saliva  increases  also.  If  the  percentage  of 
salts  in  the  blood  be  decreased,  the  percentage  of  salts  in  the 
saliva  decreases  also.''"^  ^^  ^^ 

(9)  If  the  artery  of  the  gland  be  clamped  for  20-30  minutes, 
and  the  blood  thus  completely  cut  off  from  the  gland,  on  read- 
mitting theblooda  vaso-dilation  ensues,  so  that  the  blood  rushes 
red  from  the  gland  veins,  and  this  vaso-dilation  is  accompanied 
by  a  spontaneous  secretion.  Stimulation  of  the  chorda  in  no 
way  alters  this  secretion  during  the  first  minute,  nor  until  the 
dilation  has  somewhat  diminished.  This  spontaneous  secretion 
is  a  close  duplicate  of  that  observed  by  Levy  in  the  secretion  of 
sweat.      [Experiment  V  (a).] 

Although  this  spontaneous  secretion  might,  perhaps,  be  ex- 
plained by  supposing  that  a  direct  stimulation  of  nerve-end  or 
cell  by  the  oxygen  has  taken  place,  it  seems  more  probable  to 
me  to  class  it  with  the  spontaneous  secretion  of  sweat  in  the 
horse,  following  section  of  the  cervical  sympathetic,  and  to  refer 
it  to  the  direct  effect  of  vaso-dilation. 

Anxals  N.  Y.  Acad.  Sci.,  XI,  September  13,  1898 — 24. 


358  MA  THEWS. 

f.     Conclusion.    The  Physiology  of  Salivary  Secretion. 

If  the  sympathetic  saHvary  secretion  shall  be  found  to  be  due 
to  the  action  of  contractile  tissue,  and  if  the  criticisms  of  the  ob- 
jections to  considering  the  salivary  secretion,  coincident  with 
vascular  dilation,  an  osmosis,  be  sustained  by  subsequent  work, 
the  following  conclusions  concerning  the  physiology  of  this 
secretion  may  be  drawn. 

The  salivary  glands  may  be  caused  to  secrete,  either  by  the 
action  of  contractile  tissue  under  control  of  the  sympathetic 
nerve  or  by  osmosis  under  control  of  the  vaso-dilator  nerve. 
Probably  in  normal  secretion  both  of  these  nerves  come  into 
play,  but  of  this  evidence  is  as  yet  lacking. 

Drugs,  or  other  reagents,  may  arouse  secretion  by  action  on 
either  or  both  of  these  mechanisms.  I  would  suggest  that 
secretion  following  strychnine  injection,  camphor,  pikrotoxin, 
physostigmin  (after  division  of  the  chorda)  are  due  to  the  con- 
tractions of  the  contractile  tissue.  All  of  these  drugs  stimulate 
the  nerve  centers  and  cause  a  pronounced  vaso-constriction. 
On  the  other  hand,  pilocarpine,  nicotine,  muscarine,  curare  and 
chloral  hydrate,  or  other  drugs  with  a  similar  action  on  the 
vascular  system,  probably  cause  secretion  partly  by  vaso-dila- 
tion  and  partly  by  increasing  the  permeability  of  the  gland  mem- 
branes. Such  drugs  work  through  an  osmotic  mechanism.  A 
third  class  of  drugs,  such  as  quinine,  atropine,  hydrochloric  acid 
or  sodium  carbonate  may  produce  vaso-dilation,  but  probably  act, 
also,  on  the  gland  cells  in  such  manner  as  to  diminish  their  per- 
meability- Most  of  the  work  which  has  hitherto  been  done 
upon  the  action  of  drugs  on  salivary  secretion  needs  to  be  re- 
peated with  the  possibility  in  mind  that  the  chorda  and  sym- 
pathetic induce  secretion  in  these  different  ways. 

The  osmotic  mechanism  of  secretion  in  the  salivary  glands  is 
probably  dependent  on  the  condition  of  the  gland  and  capillary 
membranes,  upon  the  composition  of  the  blood,  upon  the  rate 
of  flow  of  the  blood  and  the  character  and  amount  of  hylogens 
present  within  the  gland.  The  evidence  that  the  course  of  os- 
mosis is  controlled  by  the  action  of  nerves  directly  on  the  gland 


SECRETION  PHYSIOLOGY.  359 

cells  is  open  to  serious  criticism.  That  chorda  salivary  secre- 
tion can  ensue  without  vaso-dilation  may  be  seriously  doubted, 
not  only  for  the  reasons  already  stated,  but  because  in  the 
pancreas  there  is  good  reason  to  believe  that  secretion  can  not 
take  place  without  vaso-dilation.    (See  p.  361.) 

V.  SOME  OTHER  SECRETIONS. 

The  submaxillary  gland,  considered  in  the  foregoing  pages, 
may  be  taken  as  a  type  of  all  the  salivary  glands,  as  each  pos- 
sesses a  dilator  secretory  nerve,  and  a  constrictor,  sympathetic 
secretory  nerve.  I  wish  now  to  consider  some  other  secretion  in 
the  light  of  the  conclusions  derived  from  the  physiology  of  the 
submaxillar}^ 

a.     The  Physiology  of  Sweat  Secretion. 

There  is  reason  to  believe  that  the  mammalian  sweat  glands 
also  have  a  double  mechanism  of  secretion,  a  muscular  and  an 
osmotic.  These  glands  are  surrounded  by  a  sheath  of  muscle 
fibres  lying,  like  those  of  the  skin  glands  of  amphibia,  be- 
tween the  cells  and  the  basement  membrane.  From  the  obser- 
vations of  Ranvier,  Joseph  and  others,  who  have  shown  that 
upon  stimulation  of  the  sciatic  this  muscle  contracts,  there  can 
be  little  doubt  that  a  secretion  may  thus  be  formed.  Probably 
sweat  secretions  ensuing  coincident  with  vaso-constriction,  upon 
the  injection  of  strychnine,  upon  stimulation  of  the  sciatic  in  the 
amputated  limb  or  after  compression  of  the  blood  vessels  is  due 
to  this  mechanism. 

On  the  other  hand,  certain  secretions  of  sweat  are  too  copi- 
ous to  be  due  to  muscular  constriction  of  the  gland.  That 
those  secretions  probably  fall  under  the  second,  or  osmotic, 
mechanism  is  shown  by  the  following  facts  : 

(i)  The  coincidence  of  vaso-dilation  and  sweat  secretion. 
Most  sweat  secretions  are  normally  accompanied  by  vaso-dila- 
tion. If  the  cervical  sympathetic  of  the  horse  be  severed, 
strong  hyperaemia  and  sweating  occurs  on  the  side  of  the  neck 
the  nerve  governs.      This  sweating  ensuing  after  nerve  division 


360  MATHEWS. 

can  hardly  be  explained,  I  think,  on  the  basis  of  secretory  cell 
activity. 

(2)  Pilocarpine,  which  does  not  cause  contraction  of  the  mus- 
cular sheath,  causes  a  profuse  secretion. 

(3)  The  vaso-motor  and  secretory  fibres  in  the  cat  follow  the 
same  paths. 

(4)  Pilocarpine  causes  sweat  secretions  fourteen  days  after 
nerve  degeneration. 

(5)  If  the  blood  supply  be  cut  off,  on  readmitting  the  blood 
after  30  minutes,  a  spontaneous  secretion  occurrs."*^  The  sim- 
ilar secretion  in  the  submaxillary  is  invariably  accompanied  by 
vaso-dilation. 

(6)  Increasing  the  capillary  blood  pressure  or  drinking  large 
quantities  of  water  increases  secretion. 

The  facts,  as  far  as  they  go,  are  the  same  as  those  observed 
in  the  cerebral  salivary  secretions  and  pancreatic  secretion. 
They  justify  us,  I  believe,  in  classing  all  three  secretions  in  the 
same  category.  That  these  sweat  secretions  are  of  an  osmotic 
character  would  thus  be  indicated.  That  other  sweat  secretions 
are  due  to  muscle  there  can  be  little  doubt. 

b.  The  Secretion  of  the  Pancreas. 

Secretion  of  the  pancreas  is  normally  accompanied  by  vaso- 
dilation. In  its  relation  to  atropine,  its  increased  content  of  or- 
ganic bodies  coincident  with  an  increased  rate  of  flow,  and  in 
taking  place  after  compression  of  the  aorta,  pancreatic  secretion 
resembles  the  submaxillary  secretion  on  stimulation  of  the 
chorda  tympani.  There  is  reason  to  believe,  however,  that  the 
pancreas  cannot  secrete  unless  the  blood  vessels  dilate.  Thus 
the  means  employed  by  Pawlow,''''  Mett^^  and  Kudrewetsky^-  to 
give  the  vagi  a  secretory  function  are  just  the  means  used  by 
Bowditch,  Luchsinger  and  others^*^  to  give  the  sciatic  and  other 
mixed  dilator  and  constrictor  nerves  a  dilator  action.  These 
authors  either  cut  the  vagi  and  splanchnics,  and  allowed  them  to 
degenerate  three  or  four  days,  or  else  they  stimulated  them 
with  rythmic  induction  shocks,  at  the  rate  of  one  per  second 
after  division  of  the  cervical  cord.      There  are  two  possible  ex- 


SECRETION  PHYSIOLOGY.  361 

planations  of  the  fact  that  stimulation  of  the  normal  nerve  with 
the  cord  undivided  causes  no  secretion.  Either  the  nerve  carries 
inhibitory  secretory  as  well  as  secretoiy  fibres,  or  stimulation 
of  the  nerve  is  unable  to  cause  a  secretion  without  vaso-dilation. 
The  first  alternative  Heidenhain  has  particularly  combatted  in 
the  case  of  the  submaxillary,  and  it  appears  to  me  lacking  all 
proper  experimental  basis.  The  second  alternative  is  probably 
the  true  explanation,  for  the  reason  that  stimulation  of  the  nor- 
mal nerve  below  the  cardiac  branches  causes  no  alteration  in 
blood  pressure,  and  for  the  reason  that  the  treatment  to  which 
the  nerve  is  subjected  is  calculated  to  give  it  a  dilator  action. 
If  this  be  true  the  pancreas  would  appear  fundamentally  differ- 
ent from  the  salivary  glands,  unless,  as  I  have  endeavored  to 
show,  the  latter  are,  also,  in  reality,  unable  to  secrete  on  stim- 
ulation of  the  chorda  or  other  cerebral  nerve,  unless  vaso-dila- 
tion ensues. 

Further  evidence  of  the  dependence  of  pancreatic  secretion 
on  vaso-dilation  is  furnished  by  the  action  of  pilocarpine,  chloral 
hydrate^^  and  curare,  drugs  which  cause  vaso-dilation  and  secre- 
tion, and  by  str}'Xhnine,^^  or  digitalis,  drugs  which  cause  vaso- 
constriction and  inhibit  secretion.  Heidenhain, ^^  also,  has 
observed  a  close  correspondence  between  vaso-dilation  and 
secretion,  and  between  vaso-constriction  and  the  cessation  of 
secretion.  This  parallelism  between  vaso-dilation  and  secretion 
can  not  be  accidental.  It  indicates,  I  beheve,  that  the  dilation 
is  the  cause  of  the  secretion,  other  things  being  normal. 

VI.     GENERAL  CONCLUSION. 

We  have  now  considered  the  evidences  of  the  existence  of 
secretory  nerves,  and  the  reasons  for  believing  that  secretion  is 
a  function  of  the  gland  cells.  While  readily  admitting  the  pos- 
sibilities that  secretion  may  in  certain  instances  be  a  function  of 
the  gland  cell,  controlled  by  the  action  on  it  of  secretory  nerve 
fibres,  we  have  seen  reason  to  believe  that  certainly  many  so- 
called  secretions  are  due  not  to  the  gland  cell,  but  to  the  action 
of  contractile  tissue  either  within  or  about  the  p;land.      Among 


362  MATHEWS. 

such  secretions  are  the  sahvary  secretions  following  stimulation 
of  the  sympathetic,  certain  secretions  of  sweat,  the  secretion  of 
the  cephalopod  salivary  glands  and  of  the  skin  glands  of  am- 
phibia. 

Whether  those  secretions  which  are  normally  accompanied  by 
vaso-dilation,  such,  for  instance,  as  the  salivary  secretions  follow- 
ing stimulation  of  the  cerebral  nerves  and  the  secretions  of  the 
alimentary  tract  and  its  appendages,  are  governed  by  nerves  act- 
ing directly  on  the  gland  cells,  or  indirectly  through  the  vascu- 
lar system,  cannot  with  certainty  be  said.  But  I  believe  it  has 
been  shown  in  the  present  paper  that  the  evidence  which  has 
hitherto  been  offered  that  such  secretions  are  controlled  by 
nerve  action  on  the  gland  cell  is  open  to  serious  criticism.  The 
remarkable  parallelism  between  the  hypothetical  secretory  and 
vaso-dilator  fibres,  the  close  dependence  of  such  secretions  on 
the  vascular  system,  the  general  features  of  such  secretions  and 
the  structure  of  glands,  all  indicate,  I  believe,  that  osmosis  is 
the  essential  cause  of  these  secretions,  and  that  they  are  con- 
trolled by  the  action  of  nerves  on  the  vascular  system.  No 
one  would  deny  that  the  course  of  these  secretions  is  modified 
by  the  condition  of  the  gland  or  capillary  wall,  and  that  that 
condition  is  easily  affected  by  drugs,  but  that  nerve  action  di- 
rectly affects  that  condition,  I  do  not  believe  the  evidence 
entitles  us  to  say. 

Probably  the  study  of  these  secretions  from  the  standpoint  of 
osmosis  will  bring  to  light  facts  difficult  to  reconcile  with  our 
present  knowledge  of  osmosis.  But  while  our  knowledge  of  the 
latter  process  through  membranes  undergoing  chemical  change, 
such  as  gland  membranes,  remains  in  its  present  fragmentary 
state,  I  do  not  believe  that  we  are  justified  in  assuming  a  special 
sort  of  secretory  activity  on  the  part  of  the  gland,  or  capillary 
cell,  unless  the  facts  are  certainly  irreconcilable  with  any  other 
hypothesis. 

In  short,  while  fully  admitting  the  possibility  that  nerves  may 
act  on  gland  cells,  in  some  way  affecting  osmosis  through  them, 
it  appears  to  me  that,  in  the  present  state  of  our  knowledge  of 
secretion,  the  assumption  of  a  particular  secretory  function  of 


SECRETION  PHYSIOLOGY.  363 

cells,  and  of  special  secretory  nerves,  is  unwarranted,  unneces- 
sary, and,  in  certain  particular  cases,  opposed  to  the  phenomena 
of  the  secretion  itself. 


SUMMARY  OF  RESULTS. 

(i)  The  sympathetic  nerve  induces  salivary  secretion  by 
acting  on  contractile  tissue  in  the  glands  and  thus  causing  a 
compression  of  ducts  and  alveoli. 

(2)  The  chorda  tympani,  or  other  dilator  salivary,  secretory 
nerve  probably  causes  secretion  by  its  dilator  action  on  the  blood 
vessels,  thus  increasing  osmosis. 

(3)  The  evidence  that  the  chorda  tympani  acts  on  the  gland 
cells  is  open  to  serious  objections,  as  follows  : 

{a)  Atropine  probably  acts  directly  on  the  gland  cells  and 
capillary  endothelium,  diminishing  their  permeability. 

ip)  The  post-mortem  chorda  salivary  secretion  is  possibly 
due  to  a  back  flow  of  blood  from  the  veins  owing  to  a  dilation 
of  the  capillaries. 

(it)  The  increased  content  of  organic  matter  in  a  secretion 
coincident  with  an  increased  rate  of  secretion  is  of  little  value 
as  evidence  of  secretory  nerves,  because  (i)  saliva  is  generally 
not  a  true  solution,  and  (2)  a  weak  stimulus  probably  arouses 
but  a  portion  of  the  gland. 

id)  The  evidence  derived  from  the  action  of  nicotine  and 
the  degenerated  chorda  tympani  that  secretion  may  ensue  on 
stimulation  of  the  chorda  without  vaso-dilation  is  of  doubtful 
value,  because  of  an  erroneous  method  of  determining  that 
vaso-dilation  had  not  occurred. 

(4)  The  sweat  glands  and  the  amphibian  skin  glands,  like  the 
salivary  glands,  receive  a  double  nerve  supply  and  probably  pos- 
sess a  double  mechanism  of  secretion,  /.  e.,  a  muscular  and  an 
osmotic. 

(5)  Whether  secretory  nerves  exist  or  whether  secretion  is 
ever  a  function  of  the  gland  cell  must  be  considered  at  present 
an  open  question. 

(6)  The  thoracic  lymph  flow  in  dogs  reacts  to  nerve  stimula- 


364  MATHEWS. 

tion  and  drugs  very  similar  to  pancreatic  secretion.  It  is  in- 
creased by  rhythmical  stimulation  of  the  vagi  after  division  of 
the  cervical  cord  and  by  pilocarpine  and  chloral  hydrate,  and 
decreased  by  atropine. 

Columbia  University,  April,  1898. 

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78.  von  Wittich.  Virchow^ s  Arch.  f.  Path.  Anat.  u.  Phys., 
XXXVII. 


Date  Due 

i»Uk  \  Q 

'4a 

^6  J« 

>  lAin 

Aiifi  •? 

MU»3     f 

1944 

(|) 

QP190 

Mathev/s 


M42 


■  • 


